Cyclic AMP-specific phosphodiesterase inhibitors

ABSTRACT

Novel pyrrolidine compounds that are potent and selective inhibitors of PDE4, as well as methods of making the same, are disclosed. Use of the compounds in the treatment of inflammatory diseases and other diseases involving elevated levels of cytokines, as well as central nervous system (CNS) disorders, also is disclosed.

CROSS REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of U.S. patent application Ser. No.09/471,846, filed Dec. 23, 1999, now U.S. Pat. No. 6,258,833 pending.

FIELD OF INVENTION

The present invention relates to a series of compounds that are potentand selective inhibitors of cyclic adenosine 3′,5′-monophosphatespecific phosphodiesterase (cAMP specific PDE). In particular, thepresent invention relates to a series of novel pyrrolidine compoundsthat are useful for inhibiting the function of cAMP specific PDE, inparticular, PDE4, as well as methods of making the same, pharmaceuticalcompositions containing the same, and their use as therapeutic agents,for example, in treating inflammatory diseases and other diseasesinvolving elevated levels of cytokines and proinflammatory mediators.

BACKGROUND OF THE INVENTION

Chronic inflammation is a multi-factorial disease complicationcharacterized by activation of multiple types of inflammatory cells,particularly cells of lymphoid lineage (including T lymphocytes) andmyeloid lineage (including granulocytes, macrophages, and monocytes).Proinflammatory mediators, including cytokines, such as tumor necrosisfactor (TNF) and interleukin-1 (IL-1), are produced by these activatedcells. Accordingly, an agent that suppresses the activation of thesecells, or their production of proinflammatory cytokines, would be usefulin the therapeutic treatment of inflammatory diseases and other diseasesinvolving elevated levels of cytokines.

Cyclic adenosine monophosphate (cAMP) is a second messenger thatmediates the biologic responses of cells to a wide range ofextracellular stimuli. When the appropriate agonist binds to specificcell surface receptors, adenylate cyclase is activated to convertadenosine triphosphate (ATP) to cAMP. It is theorized that the agonistinduced actions of cAMP within the cell are mediated predominately bythe action of cAMP-dependent protein kinases. The intracellular actionsof cAMP are terminated by either a transport of the nucleotide to theoutside of the cell, or by enzymatic cleavage by cyclic nucleotidephosphodiesterases (PDEs), which hydrolyze the 3′-phosphodiester bond toform 5′-adenosine monophosphate (5′-AMP). 5′-AMP is an inactivemetabolite. The structures of cAMP and 5′-AMP are illustrated below.

Elevated levels of CAMP in human myeloid and lymphoid lineage cells areassociated with the suppression of cell activation. The intracellularenzyme family of PDEs, therefore, regulates the level of cAMP in cells.PDE4 is a predominant PDE isotype in these cells, and is a majorcontributor to cAMP degradation. Accordingly, the inhibition of PDEfunction would prevent the conversion of cAMP to the inactive metabolite5′-AMP and, consequently, maintain higher cAMP levels, and, accordingly,suppress cell activation (see Beavo et al., “Cyclic NucleotidePhosphodiesterases: Structure, Regulation and Drug Action,” Wiley andSons, Chichester, pp. 3-14, (1990)); Torphy et al., Drug News andPerspectives, 6, pp. 203-214 (1993); Giembycz et al., Clin. Exp.Allergy, 22, pp. 337-344 (1992)).

In particular, PDE4 inhibitors, such as rolipram, have been shown toinhibit production of TNFα and partially inhibit IL-1β release bymonocytes (see Semmler et al., Int. J. Immunopharmacol., 15, pp.409-413, (1993); Molnar-Kimber et al., Mediators of Inflammation, 1, pp.411-417, (1992)). PDE4 inhibitors also have been shown to inhibit theproduction of superoxide radicals from human polymorphonuclearleukocytes (see Verghese et al., J. Mol. Cell. Cardiol., 21 (Suppl. 2),S61 (1989); Nielson et al., J. Allergy Immunol., 86, pp. 801-808,(1990)); to inhibit the release of vasoactive amines and prostanoidsfrom human basophils (see Peachell et al., J. Immunol., 148, pp.2503-2510, (1992)); to inhibit respiratory bursts in eosinophils (seeDent et al., J. Pharmacol., 103, pp. 1339-1346, (1991)); and to inhibitthe activation of human T-lymphocytes (see Robicsek et al., Biochem.Pharmacol., 42, pp. 869-877, (1991)).

Inflammatory cell activation and excessive or unregulated cytokine(e.g., TNFα and IL-1β) production are implicated in allergic,autoimmune, and inflammatory diseases and disorders, such as rheumatoidarthritis, osteoarthritis, gouty arthritis, spondylitis, thyroidassociated ophthalmopathy, Behcet's disease, sepsis, septic shock,endotoxic shock, gram negative sepsis, gram positive sepsis, toxic shocksyndrome, asthma, chronic bronchitis, adult respiratory distresssyndrome, chronic pulmonary inflammatory disease, such as chronicobstructive pulmonary disease, silicosis, pulmonary sarcoidosis,reperfusion injury of the myocardium, brain, and extremities, fibrosis,cystic fibrosis, keloid formation, scar formation, atherosclerosis,transplant rejection disorders, such as graft vs. host reaction andallograft rejection, chronic glomerulonephritis, lupus, inflammatorybowel disease, such as Crohn's disease and ulcerative colitis,proliferative lymphocyte diseases, such as leukemia, and inflammatorydermatoses, such as atopic dermatitis, psoriasis, and urticaria.

Other conditions characterized by elevated cytokine levels include braininjury due to moderate trauma (see Dhillon et al., J. Neurotrauma, 12,pp. 1035-1043 (1995); Suttorp et al., J. Clin. Invest., 91, pp.1421-1428 (1993)), cardiomyopathies, such as congestive heart failure(see Bristow et al., Circulation, 97, pp. 1340-1341 (1998)), cachexia,cachexia secondary to infection or malignancy, cachexia secondary toacquired immune deficiency syndrome (AIDS), ARC (AIDS related complex),fever myalgias due to infection, cerebral malaria, osteoporosis and boneresorption diseases, keloid formation, scar tissue formation, andpyrexia.

In particular, TNFα has been identified as having a role with respect tohuman acquired immune deficiency syndrome (AIDS) results from theinfection of T-lymnphocytes with Human Immunodeficiency Virus (HIV).Although HIV also infects and is maintained in myeloid lineage cells,TNF has been shown to upregulate HIV infection in T-lymphocytic andmonocytic cells (see Poli et al., Proc. Natl. Acad. Sci. USA, 87, pp.782-785, (1990)).

Several properties of TNFα, such as stimulation of collagenases,stimulation of angiogenesis in vivo, stimulation of bone resorption, andan ability to increase the adherence of tumor cells to endothelium, areconsistent with a role for TNF in the development and metastatic spreadof cancer in the host. TNFα recently has been directly implicated in thepromotion of growth and metastasis of tumor cells (see Orosz et al., J.Exp. Med., 177, pp. 1391-1398, (1993)).

PDE4 has a wide tissue distribution. There are at least four genes forPDE4 of which multiple transcripts from any given gene can yield severaldifferent proteins that share identical catalytic sites. The amino acididentity between the four possible catalytic sites is greater than 85%.Their shared sensitivity to inhibitors and their kinetic similarityreflect the functional aspect of this level of amino acid identity. Itis theorized that the role of these alternatively expressed PDE4proteins allows a mechanism by which a cell can differentially localizethese enzymes intracellularly and/or regulate the catalytic efficiencyvia post translational modification. Any given cell type that expressesthe PDE4 enzyme typically expresses more than one of the four possiblegenes encoding these proteins.

Investigators have shown considerable interest in the use of PDE4inhibitors as anti-inflammatory agents. Early evidence indicates thatPDE4 inhibition has beneficial effects on a variety of inflammatorycells such as monocytes, macrophages, T-cells of the Th-1 lineage, andgranulocytes. The synthesis and/or release of many proinflammatorymediators, such as cytokines, lipid mediators, superoxide, and biogenicamines, such as histamine, have been attenuated in these cells by theaction of PDE4 inhibitors. The PDE4 inhibitors also affect othercellular functions including T-cell proliferation, granulocytetransmigration in response to chemotoxic substances, and integrity ofendothelial cell junctions within the vasculature.

The design, synthesis, and screening of various PDE4 inhibitors havebeen reported. Methyl-xanthines, such as caffeine and theophylline, werethe first PDE inhibitors discovered, but these compounds arenonselective with respect to which PDE is inhibited. The drug rolipram,an antidepressant agent, was one of the first reported specific PDE4inhibitors. Rolipram, having the following structural formula, has areported 50% Inhibitory Concentration (IC₅₀) of about 200 nM (nanomolar)with respect to inhibiting recombinant human PDE4.

Investigators have continued to search for PDE4 inhibitors that are moreselective with respect to inhibiting PDE4, that have a lower IC₅₀ thanrolipram, and that avoid the undesirable central nervous system (CNS)side effects, such as retching, vomiting, and sedation, associated withthe administration of rolipram. One class of compounds is disclosed inFeldman et al. U.S. Pat. No. 5,665,754. The compounds disclosed thereinare substituted pyrrolidines having a structure similar to rolipram. Oneparticular compound, having structural formula (I), has an IC₅₀ withrespect to human recombinant PDE4 of about 2 nM. Inasmuch as a favorableseparation of emetic side effect from efficacy was observed, thesecompounds did not exhibit a reduction in undesirable CNS effects.

In addition, several companies are now undertaking clinical trials ofother PDE4 inhibitors. However, problems relating to efficacy andadverse side effects, such as emesis and central nervous systemdisturbances, remain unsolved.

Accordingly, compounds that selectively inhibit PDE4, and that reduce oreliminate the adverse CNS side effects associated with prior PDE4inhibitors, would be useful in the treatment of allergic andinflammatory diseases, and other diseases associated with excessive orunregulated production of cytokines, such as TNF. In addition, selectivePDE4 inhibitors would be useful in the treatment of diseases that areassociated with elevated cAMP levels or PDE4 function in a particulartarget tissue.

SUMMARY OF THE INVENTION

The present invention is directed to potent and selective PDE4inhibitors useful in treatment of diseases and conditions whereinhibition of PDE4 activity is considered beneficial. The present PDE4inhibitors unexpectedly reduce or eliminate the adverse CNS side effectsassociated with prior PDE4 inhibitors.

In particular, the present invention is directed to pyrrolidinecompounds having the structural formula (II):

wherein R¹ is selected from the group consisting of hydrogen, loweralkyl, bridged alkyl (e.g., norbornyl), aryl, cycloalkyl (e.g.,indanyl), a 4-, 5-, or 6-membered saturated heterocycle (e.g.,3-tetrahydrofuryl), heteroaryl, C₁₋₄alkylenearyl, C₁₋₄alkyleneOaryl,C₁₋₄alkyleneheteroaryl, C₁₋₄alkyleneHet, C₂₋₄alkylenearylOaryl,C₁₋₄alkylene bridged alkyl, C₁₋₄alkylenecycloalkyl (e.g.,cyclopentylmethyl), substituted or unsubstituted propargyl (e.g.,—CH₂C≡C—C₆H₅), substituted or unsubstituted allyl (e.g.,—CH₂CH═CH—C₆H₅), and halocycloalkyl (e.g., fluorocyclopentyl);

R² is selected from the group consisting of hydrogen, methyl, andhalo-substituted methyl, e.g., CHF₂;

R³ is selected from the group consisting of C(═O)OR⁷, C(═O)R⁷,NHC(═O)OR⁷, C₁₋₃alkyleneC(═O)OR⁸, C₁₋₃alkyleneC(═O)R⁸, C(═NH)NR⁸R⁹,C(═O)NR⁸R⁹, C(═O)-C(═O)NR⁸R₉, C(═O)C(═O)OR⁸, C₁₋₄alkyleneOR⁹, aryl,C₁₋₄alkylenearyl, C₁₋₃alkyleneheteroaryl, SO₈heteroaryl, Het, andheteroaryl;

R⁴ is selected from the group consisting of hydrogen, lower alkyl,haloalkyl, cycloalkyl, and aryl;

R⁵ is selected from the group consisting of hydrogen, lower alkyl,alkynyl, haloalkyl, hydroxy-alkyl, cycloalkyl, and aryl;

R⁶ is selected from the group consisting of hydrogen, lower alkyl, andC(═O)R⁸;

R⁷ is selected from the group consisting of lower alkyl, branched orunbranched, C₁₋₄alkylenearyl, cycloalkyl, Het, C₁₋₄alkylenecycloalkyl,heteroaryl, and aryl, each optionally substituted with one or more ofOC(═O)R⁸, C(═O)OR⁸, OR⁸, NR⁸R⁹, or SR⁸;

R⁸ and R⁹, same or different, are selected from the group consisting ofhydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, C(═O)Oalkyl,C(═O)—Oaryl, C(═O)alkyl, alkylSO₂, haloalkylSO₂, C(═O)—C₁₋₄alkylenearyl,C(═O)OC₁₋₄alkylenearyl, C₁₋₄alkylenearyl, and Het, or R⁸ and R⁹ togetherform a 4-membered to 7-membered ring;

R¹⁰ is selected from the group consisting of hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, C(═O)alkyl, C(═O)cycloalkyl, C(═O)aryl, C(═O)Oalkyl,C(═O)Ocycloalkyl, C(═O)aryl, CH₂OH, CH₂Oalkyl, CHO, CN, NO₂, and SO₂R¹¹;

R¹¹ is selected from the group consisting of alkyl, cycloalkyl,trifluoromethyl, aryl, aralkyl, and NR⁸R⁹; and

salts and solvates (e.g. hydrates thereof.

In another embodiment, the present invention is directed to pyrrolidinecompounds having a strucural formula (IIa):

wherein R¹ is selected from the group consisting of hydrogen, loweralkyl, bridged alkyl, aryl, cycloalkyl, a 4-, 5-, or 6-memberedsaturated heterocycle, heteroaryl, C₁₋₄alkylenearyl, C₁₋₄alkyleneOaryl,C₁₋₄alkyleneheteroaryl, C₁₋₄alkyleneHet, C₂₋₄alkylenearylOaryl,C₁₋₄alkylene bridged alkyl, C₁₋₄alkylenecycloalkyl, substituted orunsubstituted propargyl, substituted or unsubstituted allyl, andhalocycloalkyl;

R² is selected from the group consisting of hydrogen, methyl, andhalo-substituted methyl;

R³ is selected from the group consisting of hydrogen, C₁₋₄alkylenearyl,and C(═O)C₁₋₃alkyleneO-C₁₋₄alkylenearyl;

R⁴ is selected from the group consisting of hydrogen, lower alkyl,haloalkyl, cycloalkyl, and aryl;

R⁵ is selected from the group consisting of hydrogen, lower alkyl,alkynyl, haloalkyl, hydroxyalkyl, and aryl;

R⁶ is selected from the group consisting of hydrogen, lower alkyl, andC(═O)R⁷;

R⁷ is selected from the group consisting of lower alkyl, branched orunbranched, C₁₋₄alkylenearyl, cycloalkyl, Het, C₁₋₄alkylenecycloalkyl,heteroaryl, and aryl, each optionally substituted with one or more ofOC(═O)R⁸, C(═O)OR⁸, OR⁸, NR⁸R⁹, and SR⁸; and

R⁸ and R⁹, same or different, are selected from the group consisting ofhydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, C(═O)Oalkyl,C(═O)-alkyl, C(═O)Oaryl, alkylSO₂, haloalkylSO₂, C(═O)-C₁₋₃alkylenearyl,C(═O)OC₁₋₄alkylenearyl, C₁₋₄alkylenearyl, and Het, or R⁸ and R⁹ togetherform a 4-membered to 7-membered ring;

R¹⁰ is selected from the group consisting of hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, C(═O)alkyl, C(═O)cycloalkyl, C(═O)aryl, C(═O)Oalkyl,C(═O)Ocycloalkyl, C(═O)aryl, CH₂OH, CH₂Oalkyl, CHO, CN, NO₂, and SO₂R¹¹;and

R¹¹ is selected from the group consisting of alkyl, cycloalkyl,trifluoromethyl, aryl, aralkyl, and NR⁸R⁹; and

salts and solvates (e.g., hydrates) thereof.

The present invention also is directed to pharmaceutical compositionscontaining one or more of the compounds of structural formula (II), touse of the compounds and compositions containing the compounds in thetreatment of a disease or disorder, and to methods of ppreparingcompounds and intermediates involved in the synthesis of the compoundsof structural formula (II).

The present invention also is directed to methods of (a) treating amammal having a condition where inhibition of PDE4 provides a benefit,(b) modulating cAMP levels in a mammal, (c) reducing TNFα levels in amammal, (d) suppressing inflammatory cell activation in a mammal, and(e) inhibiting PDE4 function in a mammal by administering to the mammala therapeutically effective amount of a compound of structural formula(II) or a composition containing a composition of structural formula(II).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is directed to compounds having the structuralformula (II):

wherein R¹ is selected from the group consisting of hydrogen, loweralkyl, bridged alkyl (e.g., norbornyl), aryl, cycloalkyl (e.g.,indanyl), a 4-, 5-, or 6-membered saturated heterocycle (e.g.,3-tetrahydrofuryl), heteroaryl, C₁₋₄alkylenearyl, C₁₋₄alkyleneOaryl,C₁₋₄alkyleneheteroaryl, C₁₋₄alkyleneHet, C₂₋₄alkylenecycloalkyl,C₁₋₄alkylene bridged alkyl, C₁₋₄alkylenecycloalkyl (e.g.cyclopentylmethyl), substituted or unsubstituted propargyl (e.g.,—CH₂C≡C—C₆H₅), substituted or unsubstituted allyl (e.g.,—CH₂CH═CH—C₆H₅), and halocycloalkyl (e.g., fluorocyclopentyl);

R² is selected from the group consisting of hydrogen, methyl, andhalo-substituted methyl, e.g., CHF₂;

R³ is selected from the group consisting of C(═O)OR⁷, C(═O)R⁷,NHC(═O)OR⁷, C₁₋₃alkyleneC(═O) OR⁸, C₁₋₃alkyleneC(═O)R⁸, C(═NH)NR⁸R⁹,C(═O)NR⁸R⁹, C(═O)—C(═O)NR⁸R⁹, C(═O)C(═O)OR⁸, C₁₋₄alkyleneOR⁸, aryl,C₁₋₃alkylenearyl, C₁₋₃alkyleneheteroaryl, SO₂heteroaryl, Het, andheteroaryl;

R⁴ is selected from the group consisting of hydrogen, lower alkyl,haloalkyl, cycloalkyl, and aryl;

R⁵ is selected from the group consisting of hydrogen, lower alkyl,alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, and aryl;

R⁶ is selected from the group consisting of hydrogen, lower alkyl, andC(═O)R⁷;

R⁷ is selected from the group consisting of lower alkyl, branched orunbranched, C₁₋₄alkylenearyl, cycloalkyl, Het, C₁₋₄alkylenecycloalkyl,heteroaryl, and aryl, each optionally substituted with one or more ofOC(═O)R⁸, C(═O)OR⁸, OR⁸, NR⁸R⁹, or SR⁸;

R⁸ and R⁹, same or different, are selected from the group consisting ofhydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, C(═O)Oalkyl,C(═O)—Oaryl, C(═O)alkyl, alkylSO₂, haloalkylSO₂, C(═O)-C₁₋₄alkylenearyl,C(═O)OC₁₋₄alkylenearyl, C₁₋₄alkylenearyl, and Het, or R⁸ and R⁹ togetherform a 4-membered to 7-membered ring;

R¹⁰ is selected from the group consisting of hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, C(═O)alkyl, C(═O)cycloalkyl, C(═O)aryl, C(═O)Oalkyl,C(═O)Ocycloalkyl, C(═O)aryl, CH₂OH, CH₂Oalkyl, CHO, CN, NO₂, and SO₂R¹¹;

R¹¹ is selected from the group consisting of alkyl, cycloalkyl,trifluoromethyl, aryl, aralkyl, and NR⁸R⁹; and

salts and solvates (e.g., hydrates) thereof.

In another embodiment, the present invention is directed to pyrrolidinecompounds having a structural formula (IIa):

wherein R¹ is selected from the group consisting of hydrogen, loweralkyl, bridged alkyl, aryl, cycloalkyl, a 4-, 5-, or 6-memberedsaturated heterocycle, heteroaryl, C₁₋₄alkylenearyl, C₁₋₄alkyleneOaryl,C₁₋₄alkyleneheteroaryl, C₁₋₄alkyleneHet, C₁₋₄alkylenearylOaryl,C₁₋₄alkylene bridged alkyl, C₁₋₄alkylenecycloalkyl, substituted orunsubstited propargyl, substituted or unsubstituted allyl, andhalocycloalkyl;

R² is selected from the group consisting of hydrogen, methyl, andhalo-substituted methyl;

R³ is selected from the group consisting of hydrogen, C₁₋₄alkylenearyl,and C(═O)C₁₋₃alkyleneOC₁₋₃alkylenearyl;

R⁴ is selected from the group consisting of hydrogen, lower alkyl,haloalkyl, cycloalkyl, and aryl;

R⁵ is selected from the group consisting of hydrogen, lower alkyl,alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, and aryl;

R⁶ is selected from the group consisting of hydrogen, lower alkyl, andC(═O)R⁷;

R⁷ is selected from the group consisting of lower alkyl, branched orunbranched, C₁₋₄alkylenearyl, cycloalkyl, Het, C₁₋₄alkylenecycloalkyl,heteroaryl, and aryl, each optionally substituted with one or more ofOC(═O) R⁸, C(═O)OR⁸, OR⁸, NR⁸R⁹, and SR⁸; and

R⁸ and R⁹, same or different, are selected from the group consisting ofhydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, C(═O)Oalkyl,C(═O)-alkyl, C(═O)Oaryl, alkylSO₂, haloalkylSO₂, C(═O)-C alkylenearyl,C(═O)OC₁₋₄alkylenearyl, C₁₋₄alkylenearyl, and Het, or R⁸ and R⁹ togetherform a 4-membered to 7-membered ring;

R¹⁰ is selected from the group consisting of hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, C(═O)alkyl, C(═O)cycloalkyl, C(═O)aryl, C(═O)Oalkyl,C(═O)Ocycloalkyl, C(═O)aryl, CH₃OH, CH₃Oalkyl, CHO, CN, NO₂, and SO₂R¹¹;and

R¹¹ is selected from the group consisting of alkyl, cycloalkyl,trifluoromethyl, aryl, aralkyl, and NR⁸R⁹; and

salts and solvates (e.g., hydrates) thereof.

As used herein, the term “alkyl,” alone or in combination, is defined toinclude straight chain and branched chain saturated hydrocarbon groupscontaining one to 16 carbon atoms, either substituted or unsubstituted.The term “lower alkyl” is defined herein as an alkyl group having onethrough six carbon atoms (C₁-C₆). Examples of lower alkyl groupsinclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,isobutyl, tertiary butyl, isopentyl, n-butyl, neopentyl, n-hexyl, andthe like. The term “alkynyl” refers to an unsaturated alkyl group thatcontains a carbon-carbon triple bond.

The term “bridged alkyl” is defined herein as a C₆-C₁₆ bicyclic orpolycyclic hydrocarbon group, for example, norboryl, adamantyl,bicyclo[2.2.2]-octyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]-octyl,bicyclo[4.1.0]heptyl, bicyclo[3.1.0]hexyl, and decahydronaphthyl,substituted or unsubstituted.

The term “cycloalkyl” is defined herein to include monocyclic or fusedpolycyclic C₃-C₁₀ aliphatic hydrocarbon groups. Examples of cycloalkylgroups include, but are not limited to, cyclopropyl, cyclobutyl,cyclohexyl, decahydronaphthlene, and cyclopentyl. As used herein,“cycloalkyl” also encompasses cyclic C₃-C₇ aliphatic hydrocarbon groupsfused to an aryl ring. For example, indanyl and tetrahydronaphthalenylare cycloalkyl groups as defined herein.

An alkyl, bridged alkyl, or cycloalkyl group optionally can besubstituted with one or more, typically one to three, substituents, forexample, lower alkyl, cycloalkyl, haloalkyl, e.g., CF₃—, halo, hydroxy,alkoxy, aryl, heteroaryl, and Het.

The term “alkylene” refers to an alkyl group having a substituent. Forexample, the term “C₁₋₃alkylenecycloalkyl” refers to an alkyl groupcontaining one to three carbon atoms, and substituted with a cycloalkylgroup. An example of “C₁₋₃alkylenearyl” is benzyl.

The term “haloalkyl” is defined herein as an alkyl group substitutedwith one or more halo substituents, either fluro, chloro, bromo, iodo,or combinations thereof. Similarly, “halocycloalkyl” and “haloaryl” aredefined as a cycloalkyl or an aryl group having one or more halosubstituents.

The term “aryl,” alone or in combination, is defined herein as amonocyclic or polycyclic aromatic group, preferably a monocyclic orbicyclic aromatic group, e.g., phenyl or naphthyl, that can beunsubstituted or substituted, for example, with one or more, and inparticular one to three, substituents selected from halo, alkyl, phenyl,substituted phenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl,haloalkyl, nitro, amino, alkylamino, acylamino, alkylthio,alkylsulfinyl, and alkylsulfonyl. Exemplary aryl groups include phenyl,naphthyl, biphenyl, tetrahydronaphthyl, indanyl, 2-chlorophenyl,3-chloreophenyl, 4-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl,2-methylphenyl, 4-methoxyphenyl, and the like.

The term “heteroaryl” is defined herein as a monocyclic or bicyclic ringsystem containing one or two aromatic rings and containing at least onenitrogen, oxygen, or sulfur atom in an aromatic ring, and which can beunsubstituted or substituted, for example, with one or more, and inparticular one to three, substituents, like halo, alkyl, hydroxy,hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, aryl, haloaryl, nitro,amino, alkylamino, acylamino, alkylthio, alkylsulfinyl, andalkylsulfonyl. Examples of heteroaryl groups include thienyl, furyl,pyridyl, oxazolyl, 1,2,4-oxadiazol-3-yl, quinolyl, isoquinolyl, indolyl,triazolyl, isothiazolyl, isoxazolyl, imidizolyl, benzothiazolyl,pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.

The terms “heterocycle” and “Het” are defined as a 4-, 5-, or 6-memberednonaromatic ring having one or more, typically one to three, heteroatomsselected from oxygen, nitrogen, and sulfur present in the ring, andoptionally substituted with alkyl, halo, aryl, alkoxy, C₁₋₃alkyleneHet,C₁₋₃alkyleneamino, C₁₋₃alkylenealkylamino, and haloaryl. Nonlimitingexamples include tetrahydrofuran, tetrahydropyran, piperidine,piperazine, sulfolane, morpholine, 1,3-dioxolane, tetrahydropyran,dioxane, trimethyleneoxide, and the like.

The term “halogen” or “halo” is defined herein to include fluorine,chlorine, bromine, and iodine.

The term “alkoxyl” and “aryloxy” are defined as —OR, wherein R is alkylor aryl, respectively.

The term “alkoxyalkyl” is defined as an alkoxy group appended to analkyl group.

The term “propargyl” is defined as R—C≡C—CH₂—, wherein R is hydrogen,lower alkyl, haloalkyl, cycloalkyl, substituted or unsubstituted aryl,or substituted or unsubstituted heteroaryl.

The term “allyl” is defined as R—CH═CHCH₂—, wherein R is hydrogen, loweralkyl, haloalkyl, cycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “hydroxy” is defined as —OH.

The term “hydroxyalkyl” is defined as a hydroxy group appended to analkyl group.

The term “amino” is defined as —NH₂.

The term “alkylamino” is defined as —NR₂ wherein at least one R is alkyland the second R is alkyl or hydrogen.

The term “acylamino” is defined as RC(═O)NH, wherein R is alkyl or aryl.

The term “nitro” is defined as —NO₂.

The term “alkylthio” is defined as —SR, where R is alkyl.

The term “alkylsulfinyl” is defined as R—S(O)₂, where R is alkyl.

The term “alkylsulfonyl” is defined as R—S(O₃), where R is alkyl.

In preferred embodiments, R⁵ is methyl, R⁷ is methyl or benzyl, R² ismethyl or difluoromethyl, R⁴ is selected from the group consisting ofhydrogen, methyl, trifluoromethyl, cyclopropyl, benzyl, and phenyl, andR is selected from the group consisting of hydrogen, acetyl, andbenzoyl. Preferably, R⁴ is selected from the group consisting of

Preferably, R³ is selected from the group consisting of

wherein Ac is CH₃C(═O) and tBu is C(CH₃)₃.

In most preferred embodiments, R¹ is selected from the group consistingof cyclopentyl, benzyl, tetrahydrofuryl, indanyl, norbornyl, phenethyl,phenylbutyl, methylenecyclopropyl, methylenetetrahydrofuryl,ethylenethienyl, C₁₋₄alkylenecyclopentyl, methyleneindanyl,C₁₋₄alkylenephenyl, phenylpropargyl, phenylallyl,3-(4-chlorophenyl)-(1,2,4-oxadiazol-5-yl)methyl, C₁₋₄alkylenephenoxy,C₁₋₄alkylenebyphenyl, C₁₋₄alkylenecyclohexyl, pyranyl, methylene bridgedalkyl, tetrahydronaphtyl, decahydronaphthyl, and C₁₋₄alkyl, wherein R¹is optionally substituted with one or more phenyl, hydroxy, methoxy,methyl, ethyl, trifluoromethyl, fluoro, phenoxy, t-butyl, methoxy,cyclopropyl, and halophenyl; R- is selected from the group consisting ofmethyl and difluoromethyl; R³ is selected from the group consisting ofCO₂CH₃, C(═O)CH₂OH, C(═O)CH(CH₃)—OH, C(═O)C(CH₃)₂OH, C(═O)C(═O)NH₂,C(═O)C(═O)OH, C(═O)CH₂NH₂, C(═O)CH(OH)CH₂OH, C(═O)CH(OH)CH₂CH₂CH₃,

R⁴ is hydrogen; R⁵ is methyl; R⁶ is hydrogen; and R⁸ and R⁹,independently, are selected from the group consisting of hydrogen andlower alkyl, or form a 5-membered or 6-membered ring.

The present invention includes all possible stereoisomers and geometricisomers of compounds of structural formula (II), and includes not onlyracemic compounds but also the optically active isomers as well. When acompound of structural formula (II) is desired as a single enantiomer,it can be obtained either by resolution of the final product or bystereospecific synthesis from either isomerically pure starting materialor use of a chiral auxiliary reagent, for example, see Z. Ma et al.,Tetrahedron: Asymmetry, 8(6), pages 883-888 1997). Resolution of thefinal product, an intermediate, or a starting material can be achievedby any suitable method known in the art. Additionally, in situationswhere tautomers of the compounds of structural formula (II) arepossible, the present invention is intended to include all tautomericforms of the compounds. As demonstrated hereafter, specificstereoisomers exhibit an exceptional ability to inhibit PDE4 withoutmanifesting the adverse CNS side effects typically associated with PDE4inhibitors.

In particular, it is generally accepted that biological systems canexhibit very sensitive activities with respect to the absolutestereochemical nature of compounds. (See, E. J. Ariens, MedicinalResearch Reviews, 6:451-466 (1986); E. J. Ariens, Medicinal ResearchReviews, 7:367-387 (1987); K. W. Fowler, Handbook of Stereoisomers:Therapeutic Drugs, CRC Press, edited by Donald P. Smith, pp. 35-63(1989); and S. C. Stinson, Chemical and Engineering News, 75:38-70(1997).)

For example, rolipram is a stereospecific PDE4 inhibitor that containsone chiral center. The (−)-enantiomer of rolipram has a higherpharmacological potency than the (+)-enantiomer, which could be relatedto its potential antidepressant action. Schultz et al.,Naunyn-Schmiedeberg's Arch Pharmacol, 333:23-30 (1986). Furthermore, themetabolism of rolipram appears stereospecific with the (+)-enantiomerexhibiting a faster clearance rate than the (−)-enantiomer. Krause etal., Xenobiotica, 18:561-571 (1988). Finally, a recent observationindicated that the (−)-enantiomer of rolipram (R-rolipram) is aboutten-fold more emetic than the (+)-enantiomer (S-rolipram). A. Robichaudet al., neuropharmacology, 38:289-297 (1999). This observation is noteasily reconciled with differences in test animal disposition torolipram isomers and the ability of rolipram to inhibit the PDE4 enzyme.The compounds of the present invention can have three or more chiralcenters. As shown below, compounds of a specific stereochemicalorientation exhibit similar PDE4 inhibitory activity and pharmacologicalactivity, but altered CNS toxicity and emetic potential.

Accordingly, preferred compounds of the present invention have thestructural formula (III):

The compounds of structural formula (III) are potent and selective PDE4inhibitors, and do not manifest the adverse CNS effects and emeticpotential demonstrated by stereoisomers of a compound of structuralformula (III).

Compounds of structural formula (II) which contain acidic moieties canform pharmaceutically acceptable salts with suitable cations. Suitablepharmaceutically acceptable cations include alkali metal (e.g., sodiumor potassium) and alkaline earth metal (e.g., calcium or magnesium)cations. The pharmaceutically acceptable salts of the compounds ofstructural formula (II), which contain a basic center, are acid additionsalts formed with pharmaceutically acceptable acids. Examples includethe hydrochloride, hydrobromide, sulfate or bisulfate, phosphate orhydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate,lactate, citrate, tartrate, gluconate, methanesulfonate,benzenesulphonate, and p-toluenesulphonate salts. In light of theforegoing, any reference to compounds of the present invention appearingherein is intended to include compounds of structural formula (II), aswell as pharmaceutically acceptable salts and solvates thereof.

The compounds of the present invention can be therapeuticallyadministered as the neat chemical, but it is preferable to administercompounds of structural formula (II) as a pharmaceutical composition orformulation. Accordingly, the present invention further provides forpharmaceutical formulations comprising a compound of structural formula(II), together with one or more pharmaceutically acceptable carriersand, optionally, other therapeutic and/or prophylactic ingredients. Thecarriers are “acceptable” in the sense of being compatible with theother ingredients of the formulation and not deleterious to therecipient thereof.

In particular, a selective PDE4 inhibitor of the present invention isuseful alone or in combination with a second antiinflammatorytherapeutic agent, for example, a therapeutic agent targeting TNFα, suchas ENBREL® or REMICADE®, which have utility in treating rheumatoidarthritis. Likewise, therapeutic utility of IL-1 antagonism has alsobeen shown in animal models for rheumatoid arthritis. Thus, it isenvisioned that IL-1 antagonism, in combination with PDE4 inhibition,which attenuates TNFα, would be efficacious.

The present PDE4 inhibitors are useful in the treatment of a variety ofallergic, autoimmune, and inflammatory diseases.

The term “treatment” includes preventing, lowering, stopping, orreversing the progression of severity of the condition or symptoms beingtreated. As such, the term “treatment” includes both medical therapeuticand/or prophylactic administration, as appropriate.

In particular, inflammation is a localized, protective response elicitedby injury or destruction of tissues, which serves to destroy, dilute orwall off (i.e., sequester) both the injurious agent and the injuredtissue. The term “inflammatory disease,” as used herein, means anydisease in which an excessive or unregulated inflammatory response leadsto excessive inflammatory symptoms, host tissue damage, or loss oftissue function. Additionally, the term “autoimmune disease,” as usedherein, means any group of disorders in which tissue injury isassociated with humoral or cell-mediated responses to the body's ownconstituents. The term “allergic disease,” as used herein, means anysymptoms, tissue damage, or loss of tissue function resulting fromallergy. The term “arthritic disease,” as used herein, means any of alarge family of diseases that are characterized by inflammatory lesionsof the joints atributable to a variety of etiologies. The term“dermatitis,” as used herein, means any of a large family of diseases ofthe skin that are characterized by inflammation of the skin attributableto a variety of etiologies. The term “transplant rejection,” as usedherein, means any immune reaction directed against grafted tissue(including organ and cell (e.g., bone marrow)), characterized by a lossof function of the grafted and surrounding tissues, pain, swelling,leukocytosis and thrombocytopenia.

The present invention also provides a method of modulating cAMP levelsin a mammal, as well as a method of treating diseases characterized byelevated cytokine levels.

The term “cytokine,” as used herein, means any secreted polypeptide thataffects the functions of other cells, and that modulates interactionsbetween cells in the immune or inflammatory response. Cytokines include,but are not limited to monokines, lymphokines, and chemokines regardlessof which cells produce them. For instance, a monokine is generallyreferred to as being produced and secreted by a monocyte, however, manyother cells produce monokines, such as natural killer cells,fibroblasts, basophils, neutrophils, endothelial cells, brainastrocytes, bone marrow stromal cells, epidermal keratinocytes, andB-lymphocytes. Lymphokines are generally referred to as being producedby lymphocyte cells. Examples of cytokines include, but are not limitedto, interleukin-1 (IL-1), interleukin-6 (IL-6), Tumor Necrosis Factoralpha (TNFα), and Tumor Necrosis Factor beta (TNFβ).

The present invention further provides a method of reducing TNF levelsin a mammal, which comprises administering an effective amount of acompound of structural formula TNF) to the mammal. The term “reducingTNF levels,” as used herein, means either:

a) decreasing excessive in vivo TNF levels in a mammal to normal levelsor below normal levels by inhibition of the in vivo release of TNF byall cells, including but not limited to monocytes or macrophages; or

b) inducing a down-regulation, at the translational or transcriptionlevel, of excessive in vivo TNF levels in a mammal to normal levels orbelow normal levels; or

c) inducing a down-regulation, by inhibition of the direct synthesis ofTNF as a postranslational event.

Moreover, the compounds of the present invention are useful insuppressing inflammatory cell activation. The term “inflammatory cellactivation,” as used herein, means the induction by a stimulus(including, but not limited to, cytokines, antigens or auto-antibodies)of a proliferative cellular response, the production of solublemediators (including but not limited to cytokines, oxygen radicals,enzymes, prostanoids, or vasoactive amines), or cell surface expressionof new or increased numbers of mediators (including, but not limited to,major histocompatability antigens or cell adhesion molecules) ininflammatory cells (including but not limited to monocytes, macrophages,T lymphocytes, B lymphocytes, granulocytes, polymorphonuclearleukocytes, mast cells, basophils, eosinophils, dendritic cells, andendothelial cells). It will be appreciated by persons skilled in the artthat the activation of one or a combination of these phenotypes in thesecells can contribute to the initiation, perpetuation, or exacerbation ofan inflammatory condition.

The compounds of the present invention also are useful in causing airwaysmooth muscle relaxation, bronchodilation, and prevention ofbronchoconstriction.

The compounds of the present invention, therefore, are useful intreating such diseases as arthritic diseases (such as rheumatoidarthritis), osteoarthritis, gouty arthritis, spondylitis,thyroid-associated ophthalmopathy, Behcet disease, sepsis, septic shock,endotoxic shock, gram negative sepsis, gram positive sepsis, toxic shocksyndrome, asthma, chronic bronchitis, allergic rhinitis, allergicconjunctivitis, vernal conjunctivitis, eosinophilic granuloma, adult(acute) respiratory distress syndrome (ARDS), chronic pulmonaryinflammatory disease (such as chronic obstructive pulmonary disease),silicosis, pulmonary sarcoidosis, reperfusion injury of the myocardium,brain or extremities, brain or spinal cord injury due to minor trauma,fibrosis including cystic fibrosis, keloid formation, scar tissueformation, atherosclerosis, autoimmune diseases, such as systemic lupuserythematosus (SLE) and transplant rejection disorders (e.g., graft vs.host (GvH) reaction and allograft rejection), chronicglomerulonephritis, inflammatory bowel diseases, such as Crohn's diseaseand ulcerative colitis, proliferative lymphocytic diseases, such asleukemias (e.g. chronic lymphocytic leukemia; CLL) (see Mentz et al.,Blood 88, pp. 2172-2182 (1996)), and inflammatory dermatoses, such asatopic dermatitis, psoriasis, or urticaria.

The compounds of the present invention also are useful in the treatmentof obesity, alone or in combination with a PDE3 inhibitor, and in thetreatment and prevention of nephropathy in Type 2 diabetes (see Mora etal., New England Journal of Medicine, 342, p. 441 (2000)). PDE3inhibitors are known to persons skilled in the art.

Other examples of such diseases or related conditions includecardiomyopathies, such as congestive heart failure, pyrexia, cachexia,cachexia secondary to infection or malignancy, cachexia secondary toacquired immune deficiency syndrome (AIDS), ARC (AIDS-related complex),cerebral malaria, osteoporosis and bone resorption diseases, and feverand myalgias due to infection. In addition, the compounds of the presentinvention are useful in the treatment of erectile dysfunction,especially vasculogenic impotence (Doherty, Jr. et al. U.S. Pat. No.6,127,363), diabetes insipidus and central nervous system disorders,such as depression and multi-infarct dementia.

Compounds of the present invention also have utility outside of thattypically known as therapeutic. For example, the present compounds canfunction as organ transplant preservatives (see Pinsky et al., J. Clin.Invest., 92, pp. 2994-3002 (1993)) as well.

Selective PDE4 inhibitors also can be useful in the treatment oferectile dysfunction, especially vasculogenic impotence (Doherty, Jr. etal. U.S. Pat. No. 6,127,363), diabetes insipidus (Kidney Int., 37, p.362, (1990); Kidney Int., 35, p. 494, (1989)), and central nervoussystem disorders, such as multiinfarct dementia (Nicholson,Psychopharmacology, 101, p. 147 (1990)), depression (Eckman et al.,Curr. Ther. Res., 43, p. 291 (1988)), anxiety and stress responses(Neuropharmacology, 38, p. 1831 (1991)), cerebral ischemia (Eur. J.Pharmacol., 272, p. 107 (1995)), tardive dyskinesia (J. Clin.Pharmocol., 16, p. 304 (1976)), Parkinson's disease (see Neurology, 25,p. 722 (1975); Clin. Exp. Pharmacol, Physiol., 26, p. 421 (1999)), andpremenstrual syndrome. With respect to depression, PDE4-selectiveinhibitors show efficacy in a variety of animal models of depressionsuch as the “behavioral despair” or Porsolt tests (Eur. J. Pharmacol.,47, p. 379 (1978); Eur. J. Pharmacol., 57, p. 431 (1979);Antidepressants: neurochemical, behavioral and clinical prospectives,Enna, Malick, and Richelson, eds., Raven Press, p. 121 (1981)), and the“tail suspension test” (Psychopharmacology, 85, p. 367 (1985)). Recentresearch findings show that chronic in vivo treatment by a variety ofantidepressants increase the brain-derived expression of PDE4 (J.Neuroscience, 19, p. 610 (1999)). Therefore, a selective PDE4 inhibitorcan be used alone or in conjunction with a second therapeutic agent in atreatment for the four major classes of antidepressants:electroconvulsive procedures, monoamine oxidase inhibitors, andselective reuptake inhibitors of seratonin or norepinephrine. SelectivePDE4 inhibitors also can be useful in in applications that modulatebronchodilatory activity via direct action on bronchial smooth musclecells for the treatment of asthma.

The selective PDE4 inhibitors of the present invention also can be usedin the treatment of infertility in both females and males. The presentPDE4 inhibitors elevate cAMP levels within granulosa cells, and therebyenhance gonadotropin induction of ovulation and oocyte maturation(Tsafriri et al., Dev. Biol., 178, pp. 393-402 (1996)). Furthermore, thepresent PDE4 inhibitors can be used in treatments for infertile coupleshaving abnormal semen parameters by enhancing sperm motility withoutaffecting the acrosome reaction (see Fosch et al., Hum. Reprod., 13, pp.1248-1254 (1998)).

Compounds and pharmaceutical compositions suitable for use in thepresent invention include those wherein the active ingredient isadministered to a mammal in an effective amount to achieve its intendedpurpose. More specifically, a “therapeutically effective amount” meansan amount effective to prevent development of, or to alleviate theexisting symptoms of, the subject being treated. Determination of theeffective amounts is well within the capability of those skilled in theart, especially in light of the detailed disclosure provided herein.

The term “mammal” as used herein includes males and females, andencompasses humans, domestic animals (e.g., cats, dogs), livestock(e.g., cattle, Horses, swine), and wildlife (e.g., primates, large cats,zoo specimens).

A “therapeutically effective dose” refers to that amount of the compoundthat results in achieving the desired effect. Toxicity and therapeuticefficacy of such compounds can be determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, e.g., fordetermining the LD₅₀ (the dose lethal to 50% of the population) and theED₅₀ (the dose therapeutically effective in 50% of the population). Thedose ratio between toxic and therapeutic effects is the therapeuticindex, which is expressed as the ratio between LD₅₀ and ED₅₀. Compoundswhich exhibit high therapeutic indices are preferred. The data obtainedfrom such data can be used in formulating a dosage range for use inhumans. The dosage of such compounds preferably lies within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. The dosage can vary within this range depending upon thedosage form employed, and the route of administration utilized.

The exact formulation, route of administration, and dosage can be chosenby the individual physician in view of the patient's condition. Dosageamount and interval can be adjusted individually to provide plasmalevels of the active moiety which are sufficient to maintain thetherapeutic effects.

As appreciated by persons skilled in the art, reference herein totreatment extends to prophylaxis, as well as to treatment of establisheddiseases or symptoms. It is further appreciated that the amount of acompound of the invention required for use in treatment varies with thenature of the condition being treated, and with the age and thecondition of the patient, and is ultimately determined by the attendantphysician or veterinarian. In general, however, doses employed for adulthuman treatment typically are in the range of 0.001 mg/kg to about 100mg/kg per day. The desired dose can be conveniently administered in asingle dose, or as multiple doses administered at appropriate intervals,for example as two, three, four or more subdoses per day. In practice,the physician determines the actual dosing regimen which is mostsuitable for an individual patient, and the-dosage varies with the age,weight, and response of the particular patient. The above dosages areexemplary of the average case, but there can be individual instances inwhich higher or lower dosages are merited, and such are within the scopeof the present invention.

Formulations of the present invention can be administered in a standardmanner for the treatment of the indicated diseases, such as orally,parenterally, transmucosally (e.g., sublingually or via buccaladministration), topically, transdermally, rectally, via inhalation(e.g., nasal or deep lung inhalation). Parenteral administrationincludes, but is not limited to intravenous, intra-arterial,intraperitoneal, subcutaneous, intramuscular, intrathecal, andintraarticular. Parenteral administration also can be accomplished usinga high pressure technique, like POWDERJECT™.

For buccal administration, the composition can be in the form of tabletsor lozenges formulated in conventional manner. For example, tablets andcapsules for oral administration can contain conventional excipientssuch as binding agents (for example, syrup, accacia, gelatin, sorbitol,tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (forexample, lactose, sugar, microcrystalline, cellulose, maize-starch,calcium phosphate or sorbitol), lubricants (for example, magnesium,stearate, stearic acid, talc, polyethylene glycol or silica),disintegrants (for example, potato starch or sodium starch glycollate),or wetting agents (for example, sodium lauryl sulfate). The tablets canbe coated according to methods well known in the art.

Alternatively, the compounds of the present invention can beincorporated into oral liquid preparations such as aqueous or oilysuspensions, solutions, emulsions, syrups, or elixirs, for example.Moreover, formulations containing these compounds can be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations can contain conventional additives, suchas suspending agents, such as sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxyethylcellulose,hydroxy-propylmethylcellulose, carboxymethyl cellulose, aluminumstearate gel, and hydrogenated edible fats; emulsifying agents, such aslecithin, sorbitan mono-oleate, or acacia; nonaqueous vehicles (whichcan include edible oils), such as almond oil, fractionated coconut oil,oily esters, propylene glycol, and ethyl alcohol; and preservatives,such as methyl or propyl p-hydroxybenzoate and sorbic acid.

Such preparations also can be formulated as suppositories, e.g.,containing conventional suppository bases, such as cocoa butter or otherglycerides. Compositions for inhalation typically can be provided in theform of a solution, suspension, or emulsion that can be administered asa dry powder or in the form of an aerosol using a conventionalpropellant, such as dichlorodifluoromethane or trichlorofluoromethane.Typical topical and transdermal formulations comprise conventionalaqueous or nonaqueous vehicles, such as eye drops, creams, ointments,lotions, and pastes, or are in the form of a medicated plaster, patch,or membrane.

Additionally, compositions of the present invention can be formulatedfor parenteral administration by injection or continuous infusion.Formulations for injection can be in the form of suspensions, solutions,or emulsions in oily or aqueous vehicles, and can contain formulationagents, such as suspending, stabilizing, and/or dispersing agents.Alternatively, the active ingredient can be in powder form forconstitution with a suitable vehicle (e.g., sterile, pyrogen-free water)before use.

A composition in accordance with the present invention also can beformulated as a depot preparation. Such long acting formulations can beadministered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. Accordingly, thecompounds of the invention can be formulated with suitable polymeric orhydrophobic materials (e.g., an emulsion in an acceptable oil), ionexchange resins, or as sparingly soluble derivatives (e.g., a sparinglysoluble salt).

For veterinary use, a compound of formula (II), or nontoxic saltsthereof, is administered as a suitably acceptable formulation inaccordance with normal veterinary practice. The veterinarian can readilydetermine the dosing regimen and route of administration that is mostappropriate for a particular animal.

Thus, the invention provides in a further aspect a pharmaceuticalcomposition comprising a compound of the formula (II), together with apharmaceutically acceptable diluent or carrier therefor. There isfurther provided by the present invention a process of preparing apharmaceutical composition comprising a compound of formula (II), whichprocess comprises mixing a compound of formula (II), together with apharmaceutically acceptable diluent or carrier therefor.

Specific, nonlimiting examples of compounds of structural formula (II)are provided below, the synthesis of which were performed in accordancewith the procedures set forth below.

Generally, compounds of structural formula (II) can be preparedaccording to the following synthetic schemes. In each scheme describedbelow, it is understood in the art that protecting groups can beemployed where necessary in accordance with general principles ofsynthetic chemistry. These protecting groups are removed in the finalsteps of the synthesis under basic, acidic, or hydrogenolytic conditionswhich are readily apparent to those skilled in the art. By employingappropriate manipulation and protection of any chemical functionalities,synthesis of compounds of structural formula (II) not specifically setforth herein can be acomplished by methods analogous to the schemes setforth below.

Unless otherwise noted, all starting materials were obtained fromcommercial suppliers and used without further purification. Allreactions and chromatography fractions were analyzed by thin-layerchromatography on 250-mm silica gel plates, visualized with UV(ultraviolet) light I₂ (iodine) stain. Products and intermediates werepurified by flash chromatography, or reverse-phase HPLC.

The compounds of general structural formula (II) can be prepared, forexample, by first reacting a disubstituted benzaldehyde (1) with2-butanone, then following the reaction scheme illustrated below. Othersynthetic routes also are known and available to persons skilled in theart. For example, see Feldman et al. U.S. Pat. No. 5,665,754,incorporated herein by reference, for various individual reactions, andthe synthetic methods disclosed in the Intermediates and Examplespresented hereafter.

The above reaction scheme provides a compound (5) of structural formula(II), wherein R¹ and R² are determined by the starting benzaldehyde, R³is C(═O)OCH₃, R⁴ is hydrogen, R⁵ is methyl, R⁶ is hydrogen, and R⁷ ismethyl, and R¹⁰ is hydrogen. Proper selection of starting materials, orperforming conversion reactions on compound (5), provide compounds ofgeneral structural formula (II) having other recited R¹ through R⁷ andR¹⁰ substituents.

The following illustrates the synthesis of various intermediates andcompounds of structural formula (II). The following examples areprovided for illustration and should not be construed as limiting.

In the structures herein, for a bond lacking a substituent, thesubstituent is methyl, for example:

Where no substituent is indicated as attached to a carbon or a nitrogenatom, it is understood that the carbon atom contains the appropriatenumber of hydrogen atoms.

Abbreviations which are well known to one of ordinary skill in the artalso are used, e.g., “Me” for methyl, “OMs” for mesylate, “Ph” forphenyl, “CH₂Cl₂” for methylene chloride, “NNaOH” for sodium hydroxide,“EtOAc” for ethyl acetate, “NH₄OH” for ammonium hydroxide, “MeOH” formethanol, “LiOH” for lithium hydroxide, “CsCO₃” for cesium carbonate,“H₂” for hydrogen gas, “TFA” for trifluoroacetic acid, “OAc” foracetate, “Ac” for acetyl, “t-Bu” for tertiary butyl, “sat.” forsaturated, “h” for hour, “gm” for gram”, “mmol” for millimole, “eq” forequivalent, “M” for molar, and “N” for normal.

INTERMEDIATE 1 3-Cyclopropylmethoxy-4-methoxybenzaldehyde

A solution of 3-hydroxy-4-methoxybenzaldehyde (400 g, 2.63 mole) andbromomethylcyclopropane (426 g, 3.2 mole) in 1 L dimethylformamide (DMF)was stirred with potassium carbonate (K₂CO₃) (483 g, 3.5 mole) at 55° C.for 3.5 h. Then, 1 L of water was added, the mixture chilled on ice, andIntermediate 1 filtered as a white solid, (535 g, 99%). m/z 207 (MH⁺).

INTERMEDIATE 2 3-(Indan-2-yloxy)-4-methoxybenzaldehyde

Mitsunobu Procedure

A solution of 3-hydroxy-4-methoxybenzaldehyde (15.2 g, 100 mmol, 1 eq),2-indanol (12.1 g, 90 mmol, 0.9 eq), and triphenylphosphine (26.2 g, 100mmol, 1 eq) in dry THF (300 mL) was treated dropwise withdiisopropylazodicarboxylate (DIAC) (19.6 mL, 100 mmol, 1 eq). Thereaction mixture was stirred at reflux for 16 h, then cooled and dilutedwith diethyl ether (500 mL). The solution was washed with water (2×150mL), 1 M NaOH (4×125 mL), and saturated sodium chloride (NaCl) (2×100mL), dried with sodium sulfate (Na₂SO₄), and concentrated to a syrupthat solidified upon standing. The solid was suspended in Et₂O (350 mL)and stirred overnight to provide small particles. The solid wascollected by vacuum filtration and recrystallized from ethanol/water(21.4 g). The ethereal filtrate was concentrated and purified by flashchromatography (silica gel, 7.5×36 cm Biotage KP-Sil column, eluted with25% EtOAc in heptane) to yield an akkitional 5 g of Intermediate 2.

¹H NMR (300 MHz, CDCl₃) δ: 9.86 (s, 1H), 7.49-7.44 (m, 2H), 7.25-7.16(m, 4H), 6.97 (d, J=8.7 Hz, 1H), 5.29-5.22 (m, 1H), 3.89 (s, 1H), 3.45(dd, J=16.7, 6.6 Hz, 2H), 3.24 (dd, j=16.7, 3.6 Hz, 2H). ^(13C) NMR (75MHz, CDCl₃) δ: 190.9, 155.5, 147.9, 140.4, 130.0, 126.9, 126.8, 124.7,112.1, 111.0, 78.9, 56.1, 39.7.

INTERMEDIATE 3 3-(tert-Butoxy)-4-methoxybenzaldehyde

To a stirred solution of isovanillin (30.4 gm, 200 mmol) in CH₂Cl₂ (200mL) at room temperature under a nitrogen blanket was added(2-aza-1-(tert-butoxy)-3-methylbut-1-enyl)(methylethyl)amine (crude 40mL, about 200 mmol) as an alkylating agent. Every 2 hours, another molarequivalent of the alkylating agent was added until 5 equivalents totalwere added. The reaction was allowed to stir another 16 hours. TLC in3/7 EtOAc/hexane indicated the reaction was approximately 80% tocomplete. The mixture was diluted with CH₂Cl₂ (500 mL) and washed with3M NaCH (4×300 mL) to remove unreacted isovanillin. The organics weredried over magnesium sulfate MgSO₄), filtered, and concentrated in vacuoto a crude brown oil, which was flash chromatographed in 3/1hexane/EtOAc and dried in vacuo to provide pure Intermediate 3 (22.0 gm,54%).

¹H-NMR (CDCl₃, 400 MHz) δ: 9.84 (s, 1H), 7.60 (d, 1H), 7.55 (s, 1H),7.00 (d, 1H), 3.86 (s, 3H), 1.39 (s, 9H).

INTERMEDIATE 4 (2E)-3-(3-tert-Butoxy-4-methoxyphenyl)-2-methyl-acrylicAcid Ethyl Ester

Horner-Emmons Procedure

To a stirred solution of triethyl 2-phosphonopropionate (25.6 mL, 119.4mmol) in THF (120 mL) at 0° C. under a nitrogen blanket was addedlithium hexamethyldisilylamide (1M in THF, 114 mL, 114 mmol) dropwise bysyringe. After 30 minutes, a solution or Intermediate 3 (22.6 gm, 108mmol) in THF (40 mL) was added by cannulation. After 2 hours at 0° C.,TLC in 4/1 hexane/EtOAc showed complete reaction. The reaction waspartially concentrated by rotary evaporator and partitioned betweenEtOAc (500 mL) and water (500 mL). The organics were washed withsaturated NaCl (500 mL), dried (MgSO₄), filtered, and concentrated invacuo. The crude product was flash cromatographed in 9/1 hexane/EtOAc toprovide, after concentration in vacuo, Intermediate 4 (34.1 gm, 98%).

¹H-NMR (CDCl, 400 MHz) δ: 7.60 (s, 1H), 7.16 (d, 1H), 7.12 (s, 1H), 6.91(d, 1H), 3.83 (s, 3H), 2.13 (s, 3H), 1.37 (s, 9H).

INTERMEDIATE 5 (2E)-3-(3-tert-Butoxy-4-methoxyphenyl)-2-methyl-acrylicAcid

Lithiuum Hydroxide Hydrolysis Procedure

To a stirred solution of Intermediate 4 (34.1 gm, 116 mmol) in dioxane(116 mL) at room temperature under a nitrogen blanket was added asolution of LiOH monchydrate (5.87 gm, 140 mmol) in water (116 mL). Thereaction was heated at 80° C. for 2 hours, then allowed to cool to roomtemperature. The reaction then was partitioned between EtOAc (400 mL)and 1M phosphoric acid (H₃PO₄) (400 mL). The organics were isolated,washed with H₂O (400 mL) and saturated NaCl (400 mL), dried (MgSO₄),filtered, and concentrated in vacuo to provide Intermediate 5 as a whitesolid (28.2 gm, 92%)

¹H-NMR (CDCl, 400 MHz) δ: 7.66 (s, 1H), 7.20 (d, 1H), 7.18 (s, 1H), 6.92(d, 1H), 3.83 (s, 3H), 2.16 (s, 3H), 1.38 (s, 9H).

INTERMEDIATE 6(E)-4-(3-Benzyloxy-4-methoxyphenyl)-3-methylbut-3-en-2-one

Acid-catalyzed Aldol Condensation Procedure

A solution of commercially available 3-benzyloxy-4-methoxybenzaldehyde(34 g, 0.14 mol, 1 eq) and 2-butanone (50 mL, 0.56 mol, 4 eq) in dry THF(50 mL) was cooled to −4° C. Hydrogen chloride gas was passed throughthe well-stirred solution for several minutes, and the reaction mixturewas capped and stored at −4° C. for 16 h. The mixture was poured into awell stirred solution of ice-cold saturated sodium bicarbonate (NaHCO₃)(about 2 L). If necessary, the pH was adjusted to >7 with sat. NaHCO₃,and the mixture was extracted with EtOAc (3×300 mL). The EtOAc layer waswashed with NaHCO₁ (2×200 mL), water (2×200 mL), and saturated NaCl(2×200 mL), dried with Na₂SO₄, and concentrated to a syrup. Crudemixture was purified by flash chromatography (silica gel, 7.5×36 cmBiotage KP-Sil column, eluted with 25% EtOAc in heptane) to yieldIntermediate 6 (29.1 g, 70%).

¹H NMR (300 MHz, CDCl₃) δ: 7.46-7.27 (m, 6H), 7.06-6.91 (m, 3H), 3.93(s, 3H), 2.41 (s, 3H), 1.92 (d, J=1.1 Hz, 3H).

INTERMEDIATE 7(E)-4-[3-(Indan-2-yloxy)-4-methoxyphenyl]-3-methyl-but-3-en-2-one

Prepared from Intermediate 2 by the acid-catalyzed aldol condensationprocedure of Intermediate 6.

LRMS (Electrospray, positive): Da/e 323.4 (m+1).

INTERMEDIATE 8 (E)-4-(3-Bromo-4-methoxyphenyl)-3-methylbut-3-en-2-one

Prepared from 3-bromo-4-methoxybenzaldehyde by the acid-catalyzed aldolcondensation procedure of Intermediate 6.

¹H NMR (300 MHz, CDCl₃) δ: 7.66 (d, J=2.0 Hz, 1H), 7.36-7.41 (m, 2H),6.94 (d, J=8.6 Hz, 1H), 3.94 (s, 3H), 2.45 (s, 3H), 2.06 (d, J=1.1 Hz,3H).

INTERMEDIATE 9(E)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-but-3-en-2-one

Prepared from Intermediate 1 by the acid-catalyzed aldol condensationprocedure of Intermediate 6.

¹H NMR (300 MHz, CDCl₃) δ: 7.45 (br s, 1H), 7.05-6.99 (m, 2H), 6.90 (d,J=8.26 Hz, 1H), 4.81-4.75, m, 2H), 3.99 (s, 3H), 2.45 (s, 3H), 2.89 (d,J=1.1 Hz, 3H), 1.98-1.79 (m, 6H), 1.66-1.60 (m, 2H).

INTERMEDIATE 10 Ethyl(2E)-3-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylprop-2-enoate

Prepared from commercially available3-cyclopentyloxy-4-methoxybenzaldehyde by the Horner-Emmons procedure ofIntermediate 4 to yield a brown liquid (68.4 g, 100%).

¹H NMR (400 MHz, CDCl₃) δ: 7.64 (s, 1H), 7.01-6.96 (c, 2H), 6.87 (m,1H), 4.77 (m, 1H), 4.26 (q, 2H), 3.87 (s, 3H), 2.14 (s, 3H), 1.81-1.96(c, 6H), 1.59-1.63 (c, 2H), 1.34 (t, 3H). LRMS (Electrospray, positive):Da/e 305.3 (m+1).

INTERMEDIATE 11(2E)-3-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylprop-2-enoic Acid

Intermediate 10 (68.4 g; 225 mmol)was hydrolyzed by the LiOH hydrolysisprocedure of Intermediate 5 to provide Intermediate 11 as an orangesolid (55 g, 88%).

¹H NMR (400 MHz, CDCl₃) δ: 7.76 (s, 1H), 7.06-7.00 (c, 2H), 6.89 (m,1H), 4.78 (m, 1H), 3.88 (s, 3H), 2.17 (s, 3H), 1.97-1.83 (c, 6H),1.64-1.61 (c, 2H). LRMS (Electrospray, negative): Da/e 275.3 (M−1).

INTERMEDIATE 12(2E)-3-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methyl-prop-2-enoyl Chloride

Acid Chloride Procedure

To a cooled (0° C.), stirred slurry of Intermediate 11 (55 g, 199 mmol)in anhydrous CH₂Cl₂ (400 mL) was added a solution of oxalyl chloride inCH₂Cl₂ (109 mL of 2.0 M, 218 mmol, 1.1 eq.) via syringe under a calciumchloride-dried atmosphere over 10 minutes. Vigorous bubbling wasobserved. The resulting dark solution was allowed to stir at 0° C. for15 minutes, then a catalytic amount of DMF was added via syringe (0.3mL). The resulting solution was stirred at 0° C. for 0.5 hours while thebubbling subsided, then allowed to warm to room temperature and stirovernight (17 hours). The reaction was diluted with EtOAc (500 mL) andwas carefully quenched with water (250 mL). After vigorously stirringfor 1 hour, the layers were separated and the organic layer was washedwith water (400 mL) and brine (400 mL), then dried (MgSO₄), filtered,and concentrated in vacuo to provide Intermediate 12 as a brown solid(57.5 g, 98%). ¹H NMR (400 MHz, CDCl₃) δ: 7.98 (s, 1H), 7.11-7.02 (s,2H), 6.92 (m, 1H), 4.79 (m, 1H), 3.90 (s, 3H), 2.22 (s, 3H), 2.01-1.82(c, 6H), 1.68-1.62 (c, 2H).

INTERMEDIATE 13 Ethyl(2E)-3-(3-Indan-2-yloxy-4-methoxyphenyl)-2-methylprop-2-enoate

Prepared via the Horner Emmons procedure of Intermediate 4 fromIntermediate 2.

¹H NMR (400 MHz, CDCl₃) δ: 7.64 (d, 1H), 7.28-7.17 (m, 4H), 7.06 (dd,1H), 7.03 (d, 1H), 6.90 (d, 1H), 5.20 (c, 1H), 4.28 (q, 2H), 3.85 (s,3H), 3.39 (dd, 2H), 3.26 (dd, 2H), 2.16 (d, 3H), 1.36 (t, 3H).

INTERMEDIATE 14(2E)-3-(3-Indan-2-yloxy-4-methoxyphenyl)-2-methyl-prop-2-enoic Acid

Prepared from Intermediate 13 via the LiOH hydrolysis procedure ofIntermediate 5.

¹H NMR (D₆ DMSO, 400 MHz) δ: 7.56 (s, 1H), 7.25-7.11 (m, 5H), 7.06 (d,1H), 6.99 (d, 1H), 5.22 (c, 1H), 3.71 (s, 3H), 3.34 (dd, 2H), 3.03 (d,2H), 2.06 (s, 3H).

INTERMEDIATE 15(2E)-3-(3-Indan-2-yloxy-4-methoxyphenyl)-2-methylprop-2-enoyl Chloride

Prepared from Intermediate 14 via the acid chloride procedure ofIntermediate 12.

¹HMR (400 MHz, CDCl₃) δ: 8.01 (s, 1H), 7.29-6.93 (m, 7H), 5.23 (c, 1H),3.89 (s, 3H), 3.42 (dd, 2H), 3.28 (dd, 2H) 2.26 (s, 3H).

INTERMEDIATE 163-[(2E)-3-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylprop-2-enoyl](4R)-4-phenyl-1,3-oxazolidin-2-one

Oxazolidinone Acylation Procedure

To a cooled (−78° C.), overhead, mechanically stirred solution ofR-phenyl oxazolidinone (10.0 g, 61.3 mmol) in dry tetrahydrofuran (400mL) was added a solution of n-butyllithium in hexanes (27 mL of 2.5 M,1.1 eq.) via syringe under a nitrogen atmosphere. The resulting solutionwas allowed to stir at −78° C. for 0.8 hours, then a solution ofIntermediate 12 (19.9 g, 67.4 mmol, 1.1 eq.) in THF (100 mL) was addedvia cannula. After stirring at −78° C. for 15 minutes, the reaction wasallowed to slowly warm to 0° C. over 40 minutes during which time thereaction became a thick slurry. After stirring at 0° C. for 2.5 hours,the reaction was quenched with saturated, aqueous ammonium chloride(NH₄Cl) (300 mL) and the bulk of the THF was removed at reducedpressure. The residue then was extracted with chloroform (CHCl₃) (3×700mL) and the combined organic layers were washed with water (300 mL) andbrine (300 mL), then dried (MgSO₄) filtered, and concentrated in vacuoto provide about 33 g of a light orange solid. The Material wassuscended in 10% EtOAc in hexane (1.2 L) and vigorously stirredovernight. The resulting fine powdery solids were collected on a Buchnerfunnel with suction, then dried in vacuo to provide Intermediate 16 as atan powder (21.8 g, 88%).

¹H NMR (400 MHz, CDCl₃) δ: 7.41-7.37 (c, 5H), 7.06 (s, 1H), 7.01-6.97(c, 2H), 6.86 (m, 1H), 5.54 (t, 1H), 4.77-4.73 (c, 2H), 4.29 (t, 1H),3.87 (s, 3H), 2.17 (s, 3H), 1.97-1.82 (c, 6H), 1.62-1.56 (c, 2H).

INTERMEDIATE 173-[(2E)-3-(3-Indan-2-yloxy-4-methoxyphenyl)-2-methylprop-2-enoyl](4R)-4-phenyl-1,3-oxazolidin-2-one

Prepared from Intermediate 15 via the oxazolidinone acylation crocedureof Intermediate 16.

¹H NMR (400 MHz, CDCl₃) δ: 7.43-7.33 (m, 5H), 7.25-7.16 (m, 4H),7.07-7.03 (m, 2H), 6.89 (d, 1H), 5.54 (dd, 1H), 5.19 (c, 1H), 4.74 (t,1H), 4.28 (dd, 1H), 3.84 (s, 3H), 3.33 (dd, 2H), 3.24 (ddd, 2H), 2.19(d, 3H).

INTERMEDIATE 18 Ethyl(2E)-3-[4-methoxy-3-(phenylmethoxy)phenyl]-2-methylprop-2-enoate

Prepared from 3-benzyloxy-4-methoxybenzaldehyde via the Horner Emmonsprocedure of Intermediate 4.

¹H NMR (400 MHz, CDCl₃) δ: 7.56 (s, 1H), 7.44 (t, 2H), 7.36 (t, 2H),7.30 (t, 1H), 7.01 (dd, 1H), 6.95 (d, 1H), 6.90 (d, 1H), 5.18 (s, 2H),4.24 (q, 2H), 3.92 (s, 3H), 1.98 (d, 3H), 1.33 (t, 3H).

INTERMEDIATE 19(2E)-3-[4-Methoxy-3-(phenylmethoxy)phenyl]-2-methylprop-2-enoic Acid

Prepared from Intermediate 18 via the LiOH hydrolysis procedure ofIntermediate 5 and used without characterization.

INTERMEDIATE 20(2E)-3-[4-Methoxy-3-(phenylmethoxy)phenyl]-2-methylprop-2-enoyl Chloride

Prepared from Intermediate 19 via the acid chloride procedure ofIntermediate 12.

¹H MMR (400 MHz, CDCl₃) δ: 7.91 (s, 1H), 7.47-7.29 (m, 5H), 7.10 (dd,1H), 7.00 (d, 1H), 6.95 (d, 1H), 5.20 (s, 2H), 3.95 (s, 3H), 2.04 (s,3H).

INTERMEDIATE 213-{(2E)-3-[4-Methoxy-3-(phenylmethoxy)phenyl]-2-methylprop-2-enoyl}(4R)-4-phenyl-1,3-oxazolidin-2-one

Prepared from Intermediate 19 via the oxazolidinone acylarion procedureof Intermediate 16.

¹H NMR (400 MHz, CDCl₃) δ: 7.44-7.29 (m, 11H), 7.03-6.89 (m, 3H), 5.52(dd, 1H), 5.17 (s, 2H), 4.73 (dt, 1H), 4.27 (dd, 1H), 3.91 (s, 3H), 2.00(s, 3H).

INTERMEDIATE 22(2E)-3-[3-(3-tert-Butoxy-4-methoxyphenyl)-2-methylacryloyl]-4-R-phenyloxazolidin-2-one

Prepared from Intermediate 5 (25.7 gm, 97.2 mmol) via the oxazolidinoneacylation procedure of Intermediate 16 to provide Intermediate 22 as anoff white solid (39.3 gm, quantitative yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 7.42-7-33 (m, 5H), 7.16 (d, 1H), 7.02 (s,1H), 6.87 (d, 1H), 5.55 (dd, 1H), 4.73 (dd, 1H), 4.26 (dd, 1H), 3.81 (s,3H), 2.16 (s, 3H), 1.38 (s, 9H).

INTERMEDIATE 23Trans-(±)-1-[1-Benzyl-4-(3-benzyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]ethanone

Azomethine ylide Cyclization

A solution of Intermediate 6 (15 g, 50.6 mmol, 1 eq) andN-(methoxymethyl)-N-(trimethysilylmethyl)benzylamine (11.9 g, 50.6 mmol,1 eq) in CH₂Cl₂ (85 mL) at 0° C. was treated dropwise with a solution ofTFA (1 M in CH₂Cl₂, 5 mL, 5.1 mmol, 0.1 eq). After stirring at the 0° C.for 30 min., the reaction mixture was stirred at room temperature for 16h. The solution was treated with additionalN-(methoxymethyl)-N-(trimethysilylmethyl)benzylamine (6 g, 25.3 mmol,0.5 eq), stirred 1 h at room temperature, and treated for a third timewith N-(methoxymethyl)-N-(trimethysilylmethyl)benzylamine (6 g, 25.3mmol, 0.5 eq). The reaction mixture was concentrated, and the residuewas dissolved in EtOAc (500 mL). The solution was washed with 1 N HCl(2×60 mL with 10 mL sat. NaCl added), water (250 mL), 1 M NaOH (250 mL),water (250 mL), sat. NaCl (2×100 mL), dried with Na₂SO₄, andconcentrated in vacuo. The residue was purified by flash chromatography(silica gel, 7.5×36 cm Biotage KP-Sil column, eluted with 5-10% diethylether in dichloromethane) to yield Intermediate 23 as a light yellowsyrup (17.4 g, 80%).

¹H NMR (300 MHz, CDCl₃) δ: 7.44-7.22 (m, 10H), 6.81-6.72 (m, 3H), 5.14(s, 2H), 3.86 (s, 3H), 3.72-3.67 (m, 2H), 3,58 (d, J=13.0 Hz, 1H), 3.08(d, J=9.7 Hz, 1H), 2.99 (dd, J=8.9, 7.8 Hz, 1H), 2.74 (dd, J=9.1, 7.4Hz, 1H), 2.33 (d, J=9.7 Hz, 1H), 2.15 (s, 3H), 0.68 (s, 3H). ¹³C NMR (75MHz, CDCl₃) δ: 211.3, 148.41 147.4, 139.2, 137.2, 132.7, 128.51, 128.50,128.3, 127.8, 127.4, 127.0, 121.6, 115.5, 111.2, 71.0, 63.8, 60.0, 59.5,57.9, 56.0, 47.7, 25.6, 20.6.

INTERMEDIATE 24Trans-(+)-1-{1-Benzyl-4-[3-(indan-2-yloxy)-4-methoxyphenyl]-3-methylpyrrolidin-3-yl}ethanone

Prepared from Intermediate 7 by the azomethine cyclization procedure ofIntermediate 23.

¹H NMR (300 MHz, CDCl₃) δ: 7.38-7.16 (m, 9 H), 6.88 (br s, 1H), 6.78 (brs, 2H), 5.18-5.13 (m, 1H), 3.82-3.73 (m, 2H), 3.79 (s, 3H), 3.60 (d,J=13.0 Hz, 1H), 3.41-3.17 (m, 4H), 3.14 (d, J=9.7 Hz, 1H), 3.05 t, J=8.3Hz, 1H), 2.34 (t, J=8.3 Hz, 1H), 2.44 (d, J=9.7 Hz, 1H), 2.24 (s, 3H),0.86 (s, 3H).

INTERMEDIATE 25(±)-1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidine-3-carboxylicAcid Ethyl Ester

Prepared from Intermediate 10 by the azomethine ylide cyclizationreaction of Intermediate 23 to yield an amber oil (16.7 g, 61% yield).

¹H NMR (300 MHz, CDCl₃) δ: 7.39-7.23 (m, 5H, aromatic), 6.91 (s, 1H,aromatic), 6.78 (m, 2H, aromatic), 4.75 (m, 1H), 4.18 (q, 2H, OEt), 3.86(m, 1H), 3.81 (s, 3H, OCH₃), 3.75 (d, 1H, J=13.2 Hz), 3.62 (d, 1H,J=13.2 Hz) 3.20 (d, 1H, J=9.5 Hz) 3.01 (m, 1H), 2.91 (m, 1H), 2.51 (d,1H, J=9.5 Hz), 1.93-1.58 (m, 8H, cyclopentyl), 1.28 (t, 3H, OEt), 0.9(s, 3H, CH₃).

INTERMEDIATE 26Trans-(±)-1-[1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]ethanone

Prepared according to procedure set forth in U.S. Pat. No. 5,665,754.

INTERMEDIATE 27(±)-[1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-y]methanol

To a magnetically stirred solution of Intermediate (9.32 g, 21.3 mmol)in dry toluene (10 mL) at 0° C. was added diisobutylaluminum hydride (64mL, 1.0M in CH₃Cl₃, 63.9 mmol). The mixture was stirred for 30 minutesat 0° C., then at room temperature for 1 hour, and finally quenched withMeOH (20 mL). A 1.0 N hydrochloric acid HCl solution (100 mL) then wasadded, and the mixture stirred another 30 minutes. The phases wereseparated and the aqueous phase extracted with CH₂Cl₂ (2×20 mL). Theorganic phases were washed with a saturated NH₄Cl solution, dried overanhydrous Na₂SO₄, then concentrated to afford a light yellow oil product(8.28 g, 98% yield).

¹H NMR (300 MHz, CDCl₄) δ: 7.31-7.14 (m, 5H, aromatic), 6.78-6.71 (m,3H, aromatic), 4.76-4.73 (br. m, 1H), 3.79 (s, 3H, OCH₃), 3.71-3.55 (m,3H), 3.47-3.10 (m, 3H), 2.92 (d, 1H, J=9.2 Hz), 2.62 (m, 1H), 3.35-2.33(m, 2H), 1.89-1.58 (m, 8H, cyclopentyl), 0.52 (s, 3H, CH₃).

INTERMEDIATE 28(±)-1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidine-3-carboxaldehyde

A solution of oxalyl chloride (4.87 mL, 9.73 mmol) in dry CH₂Cl₂ (20 mL)was chilled to −78° C. under a nitrogen blanket, and stirred while beingtreated with a solution of dimethyl sulfoxide (DMSO, 1.38 mL, 19.5 mmol)in CH₂Cl₂ (5 mL). Gas evolution was observed. When the addition wascomplete, the solution was stirred for 5 minutes, then a solution ofintermediate 27 (3.5 g, 8.85 mmol) in CH₂Cl₂ (10 mL) was added over aperiod of 10 minutes. The mixture was stirred for 30 minutes, treatedwith triethylamine (Et₃N) (6.7 mL, 44.3 mmol), and allowed to warm toroom temperature. Water was added to the mixture, and the resultingphases separated. The aqueous phase was extracted with CH₂Cl₂ (2×50 mL)The combined organic phases were washed with brine, dried (Na₂SO₄) andconcentrated to give an oily product (3.2 g, 92%).

¹H NMR (300 MHz, CDCl₃) δ: 9.63 (s, 1H, CHO), 7.34-7.21 (m, 5H,aromatic), 6.78-6.68 (m, 3H, aromatic), 4.73 (br. m, 1H), 3.80 (s, 3H,OCH₃), 3.78-3.61 (m, 3H), 3.18-3.11 (m, 2H), 2.86-2.81 (m, 1H),2.58-2.52 (m, 1H), 2.43-2.34 (m, 2H), 1.87-1.59 (m, 8H, cyclopentyl),0.74 (s, 3H, CH₃).

INTERMEDIATE 29(±)-1-[1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]-1-hydroxypropan-2-one

To a solution of ethyl vinyl ether (0.95 mL, 9.91 mmol) in dry THF (4mL) at −78° C. was added 1.7M t-butyllithium in pentane (5.25 mL, 8.93mmol), and the resulting solution was warmed to 0° C. The color of thesolution changed from yellow Lo colorless. The resulting vinyl anionthen was cooled to −78° C., and a solution of Intermediate 28 (1.95 g,4.96 mmol) in THF (10 mL) was added dropwise. The resulting mixture wasstirred for 45 minutes, quenched with saturated NH₄Cl (15 mL), andextracted with Et₂O (3×30 mL). The combined organic extracts were driedover Na₂SO₄ and concentrated. The crude product was dissolved in Et₂Oand treated with concentrated sulfuric acid (H₂SO₄) in a separatoryfunnel while shaking vigorously. The Et₂O solution was washed with water(30 mL), with saturated NaHCO₃ (30 mL) solution, dried over Na₂SO₄, andconcentrated. The residue was purified by flash chromatography (silicagel, 20% EtOAc-hexanes) to provide Intermediate 29 as an orange oil(1.36 g, 62% yield).

¹H NMR (300 MHz, CDCl₃) δ: 7.34-7.27 (m, 5H, aromatic), 6.77-6.68 (m,3H, aromatic), 4.75-4.72 (br. m, 1H), 4.13-4.08 (m, 1H), 3.81 (s, 3H,OCH₃), 3.79-3.57 (m, 3H), 3.26 (m, 1H), 2.99 (d, 1H, J=9.2 Hz),2.69-2.64 (m, 1H), 2.39 (d, 1H, J=9.2 Hz) 2.25 (s, 3H, OCH₃), 1.94-1.59(m, 8H, cyclopentyl), 0.69 (s, 3H, CH₃).

EXAMPLE 1(±)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-(1-hydroxy-1-methylethyl)-3-methylpyrrolidine-1-carboxylicAcid Methyl Ester

To a 3.0 M solution of methylmagnesium bromide (0.6 mL, 1.8 mmol) inEt₂O at 0° C. was added a solution of Intermediate 36 (0.65 g, 1.73mmol) in dry THF (5 mL), dropwise via a syringe pump. The resultingmixture was stirred at 0° C. for 30 minutes, then at room temperaturefor 1 hour. The reaction mixture then was quenched with saturated NH₄Cl(15 mL) and extracted with Et₂O (2×10 mL). The combined organic extractswere dried over Na₂SO₄ and concentrated. The residue was purified byflash chromatography (silica gel, 20% EtOAc-hexanes, then 50%) toprovide Example 1 as an orange oil (0.37 g, 55%).

¹H NMR (300 MHz, CDCl₃) δ: 6.83-6.77 (m, 3H, aromatic), 4.75-4.74 (br.m, 1H), 3.83 (s, 3H, OCH₃), 3.96-3.50 (m, 4H), 3.73 (s, 3H, OCH₃),3.37-3.25 (m, 1H), 1.96-1.59 (m, 8H, cyclopentyl), 1.22 (s, 3H, CH₃),1.07 (s, 6H, CH₃).

INTERMEDIATE 302-[1-Benzyl-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]propan-2-ol

Intermediate 33 (0.992 g, 2.52 mmol) was dissolved in THF (7.5 mL) andthe solution was cooled to 0° C. Methylmagnesium iodide (3.0 M in ether,2.52 mL, 7.6 mmol) was added and the reaction mixture was stirred at 0°C. for 1.5 hours. Saturated NH₄Cl was added and the reaction mixture wasconcentrated in vacuo. The residue was diluted with EtOAc and theorganic layer was washed three times with saturated NaHCO₃, saturatedNaCl, then dried over Na₂SO₄ and concentrated in vacuo (0.96 g, 93%).

¹H NMR (CDCl₃, 400 MHz) δ: 7.33-7.24 (m, 5H), 6.83-6.77 (m, 3H),3.86-3.74 (m, 7H), 3.68-3.59 (dd, 2H), 3.32 (dd, 1H), 3.24 (d, 1H), 2.48(dd, 1H), 2.16 (d, 1H), 1.35-1.28 (m, 1H), 1.21-1.18 (m, 5H), 0.66-0.60(m, 2H), 0.56 (s, 3H), 0.38-0.33 (m, 2H). LRMS (Electrospray, positive):Da/e 410.5 (m+1).

INTERMEDIATE 312-[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]propan-2-ol

Intermediate 30 (0.96 g, 2.3 mmol) was dissolved in methanol (10 mL) andthe solution was treated with Pearlman's catalyst (20% Pd(OH) on carbon,200 mg) and ammonium formate (1.0 g, 15.8 mmol). The solution was heatedto reflux for 6 hours. The catalyst was removed by filtration and thesolution was concentrated in vacuo. The residue was dissolved in EtOAcand washed three times with water, saturated NaCl, dried over Na₂SO₄ andconcentrated in vacuo, (384 mg, 52%).

¹H NMR (CDCl₃, 400 MHz) δ: (6.83-6.79(m, 3H), 3.86-3.80 (m, 5H),3.75-3.66 (m, 2H), 3.57-3.51 (m, 2H), 3.22-3.17 (m, 1H), 2.78-2.67 (m,1H), 1.34-1.21 (m, 7H), 0.69 (s, 3H), 0.66-0.60 (m, 2H), 0.37-0.33 (m,2H). LRMS (Electrospray, positive): Da/e 320.3(m+1).

INTERMEDIATE 322-Benzyloxy-1-[4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(1-hydroxy-1-methylethyl)-3-(S)-methylpyrrolidin-1-yl]ethanone

Intermediate 31 (75 mg, 0.23 mmol) was dissolved in CH₂Cl₂ (1 mL) andthe solution was treated with N,N-diisopropylethylamine (DIEA) (61 μL,0.35 mmol), then cooled to 0° C. Benzyloxyacetyl chloride (55.6 μL, 0.23mmol) was added, and the solution was stirred at 0° C. for 3 hours. Thereaction mixture was diluted with CH₂Cl₂ and washed three times with 1NHCl, once with water, three times with 6% NaHCO₃, then dried with Na₂SO₄and concentrated in vacuo. The crude product (103 mg) waschromatographed with EtOAc/hexane (1:1) to provide Intermediate 32 (21mg, 19%).

¹H NMR (CDCl₃, 400 MHz) δ: 7.41-7.27 (m, 5H), 6.85-6.76 (m, 3H),4.66-4.61 (m, 2H), 4.13-4.07 (m, 2H), 3.94-3.59 (m, 7H), 3.53-3.47 (m,1H), 3.28-3.22 (m, 1H), 1.34-1.24 (m, 2H), 1.24-1.19 (m, 2), 1.14-1.11(m, 2H), 1.07-0.98 (m, 6H), 0.66-0.59 (m, 2H), 0.36-0.31 (m, 2H). LRMS(Electrospray, positive): Da/e 468.3 (m+1).

EXAMPLE 21-[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(1-hydroxy-1-methylethyl)-3-(S)-methylpyrrolidin-1-yl-2-hydroxyethanone

Intermediate 32 (21 mg, 45 μmol) was dissolved in ethanol (95%, 2 mL)and treated with Pearlman's catalyst (20% Pd(OH)₂ on carbon, 20 mg) Thesolution was subjected to 1 atmosphere of H₂ for 20 hours. The catalystwas removed by filtration and concentrated in vacuo, to afford Example 2(15 mg, 88%).

¹H NMR (CDCl₃, 400 MHz) δ: 6.87-6.80 (m, 3H), 4.20-4.09 (m, 2H),3.89-3.62 (m, 9H), 3.58-3.51 (m, 1H), 3.13-2.87 (m, 2H), 1.35-1.01 (m,10H), 0.67-0.61 (m, 2H), 0.39-0.33 (2H). LRMS (Electrospray, positive):Da/e 378.4 (m+1).

INTERMEDIATE 331-[1-Benzyl-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]ethanone

Oxalyl chloride (2.0M in CH₂Cl₂, 1.35 mL, 2.7 mmol) was added to CH₂Cl₂(4 mL) and the solution was cooled to −60° C. A solution of DMSO (0.36mL, 5.0 mmol) in CH₂Cl₂ (1.5 mL) was added slowly. This solution wasstirred for 5 minutes, then Intermediate 66 (1.06 g, 2.7 mmol) dissolvedin CH₂Cl₂ (7.5 mL) was added to the solution. The reaction was stirredfor 30 minutes at −60° C., then quenched with Et₃N (1.9 mL). The mixturewas allowed to warm to room temperature, diluted with water, and afterstirring vigorously for several minutes, the layers were separated. Theorganic layer was washed three times with 1 N HCl, three times with 6%NaHCO₃ then dried over Na₂SO₄, and concentrated in vacuo. Intermediate33 was recovered and used without purification, (0.992 g, 93%). LRMS(Electrospray, positive): Da/e 392.4 (m+1).

INTERMEDIATE 34Trans-(±)-[3-Acetyl-4-(3-benzyloxy-4-methoxyphenyl)-3-methyl]pyrrolidine-1-carboxylicAcid Methyl Ester

A solution of Intermediate 23 (17.4 g, 40.5 mmol, 1 eq) in acetonitrile(150 mL) was treated with methyl chloroformate (15.6 mL, 202.5 mmol, 5eq), then stirred at reflux 1 hour. The reaction mixture wasconcentrated, and the residue was purified by flash chromatography(silica gel, 7.5×36 cm Biotage KP-Sil column, eluted with 50-60% EtOAcin heptane) to afford Intermediate 34 as a colorless syrup (13.7 g,85%).

¹H NMR (300 MHz, CDCl) δ: 7.42-7.27 (m, 5H), 6.82 (d, J=8.8 Hz, 1H),6.69 (br d, J=8.3 Hz, 1H), 6.63 (d, J=1.8 HZ, 1H), 5.15 (s, 2H), 3.88(3, 3H), 3.84 (dd, J=16.3, 11.0 Hz, 1H), 3.73 (br s, 3H), 3.24/-3.12 (2d, J=11.31/11.0 Hz, 1H), 2.09/2.01 (2 s, 3H), 0.84 (s, 3H). ¹³C NMR (75MHz, CDCl₃) δ: 210.0/209.8 155.2, 149.0, 147.5, 137.0, 130.5/130.0,123.5, 127.8, 127.2/127.1, 121.2/121.0, 114.9/114.8, 111.5, 70.9,58.1/57.2, 55.9, 54.4/54.0, 52.5, 50.2/50.0, 48.4/-48.0, 26.3, 17.5.

INTERMEDIATE 35Trans-(±)-3-Acetyl-4-[3-(indan-2-yloxy)-4-methoxyphenyl]-3-methylpyrrolidine-1-carboxylicAcid Methyl Ester

Prepared from Intermediate 24 by the methyl chloroformate procedure ofIntermediate 34.

¹H NMR (300 MHz, CDCl₃) δ: 7.24-7.16 (m, 4H), 6.82 (d, J=8.8 Hz, 1H),6.75-6.72 (m, 2H), 5.18-5.10 (m, 1H), 3.91 (t, J=11.2 Hz, 1H), 3.80 (s,3H), 3.77-3.65 (m, 3H), 3.74 (s, 3H), 3.42-3.16 (m, 5H), 2.17 (d, J=6.8Hz, 3H), 1.04 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ: 210.1/209.9, 155.3,149.4, 146.9/146.8, 140.5/140.4, 130.5/130.0, 126.7, 124.7, 121.3/121.1,116.1/115.8, 111.9, 79.2, 58.2/57.4, 55.9, 54.7/54.2, 52.6, 50.2/50.0,48.5/48.1, 39.7, 26.6/26.5, 17.8.

INTERMEDIATE 36Trans-(±)-3-Acetyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-3-methylpyrrolidine-1-carboxylicAcid Methyl Ester

Prepared according to procedure set forth in U.S. Pat. No. 5,665,754.Racemic form of Intermediate 46.

INTERMEDIATE 37Trans-(±)-[3-Acetyl-4-(3-hydroxy-4-methoxyphenyl)-3-methyl]pyrrolidine-1-carboxylicAcid Methyl Ester

A solution of Intermediate 34 (8.7 g, 21.9 mmol) in etranol (50 mL) wasshaken for 16 hours under H₂ (50 psi) in the presence of palladium oncarbon catalyst (0.5 g, 10% Pd/C). The catalyst was filtered off througha pad of diatomaceous earth followed by a 0.22 um membrane filter. Thefiltrate was concentrated in vacuo to give Intermediate 37 as a clearsyrup (6.5 g, 97%).

¹H NMR (300 MHz, CDCl₃) δ: 6.79 (d, J=8.3 Hz, 1H), 6.74 (d, J=1.8 Hz,1H), 6.63 (br d, J=8.3 Hz, 1H), 6.04 (br s, 1H), 3.96-3.85 (m, 1H), 3.87(s, 3H), 3.75/3.73 (2 s, 3H), 3.74-3.59 (m, 3H), 3.36/3.26 (2 d,J=11.2/11.0 Hz, 1H), 2.17/2.15 (2 s, 3H), 1.01 (s, 3H). ¹³C NMR (75 MHz,CDCl₃) δ: 210.0/209.8, 155.3, 145.9/145.8, 145.5, 131.2/130.8, 119.9,114.5, 110.6, 58.1/57.2, 55.8, 54.4/53.9, 52.5, 50.3/50.1, 48.4/48.0,26.3, 17.6.

INTERMEDIATE 38Trans-3-Acetyl-4-[exo-3-(bicyclo[2.2.1]hept-2-yl-oxy)-4-methoxyphenyl]-3-methylpyrrolidine-1-carboxylicAcid Methyl Ester

Prepared by the Mitsunobu procedure of Intermediate 2 from Intermediate37 and endo-norborneol (36% yield).

¹H NMR (300 MHz, CDCl₃) δ: 6.80 (d, J=8.2 Hz, 1H), 6.66 (d, J=9.0 Hz,1H), 6.62 (s, 1H), 4.15-4.08 (m, 1H), 3.95-3.86 (m, 1H), 3.83 (s, 3H),3.74 (s, 3H) 3.73-3.60 (m, 3H), 3.37/3.28 (2 d, J=11.2/10.8 Hz, 1H),2.47 (br s, 1H), 2.32 (br s, 1H), 2.17/2.15 (2 s, 3H), 1.76-1.66 (m,2H), 1.63-1.45 (m, 3H), 1.28-1.08 (m, 3H), 1.02/1.01 (2 s, 3H). ¹³C NMR(75 MHz, CDCl₃) δ: 210.5/210.3, 155.7, 149.6, 147.4, 130.8/130.76,130.3, 120.9/120.7/120.5, 115.6/115.4/115.3/115.2, 112.2, 81.5,58.6/57.8, 56.4, 54.9/54.6, 52.9, 50.6/50.5, 49.1/49.0/48.7, 41.5, 40.4,35.8/35.7, 28.8, 26.9/26.8, 24.7/24.6, 18.2.

INTERMEDIATE 39Trans-[3-Acetyl-4-(4-methoxy-3-(1-methyl-3-phenylpropoxy)phenyl]-3-methylpyrrolidine-1-carboxylicAcid Methyl Ester

Prepared by the Mitsunobu procedure of Intermediate 2 from Intermediate37 and 4-phenyl-2-butanol.

¹H NMR (300 MHz, CDCl₃) δ: 7.29-7.15 (m, 5H), 6.82 (d, J=8.3 Hz),6.72-6.63 (m, 2H), 4.33-4.25 (m, 1H), 3.94-3.59 (m, 4H), 3.84 (s, 3H),3.74 (br s, 3H), 3.36/3.27 (2 dd, J=11.2, 3.0/10.9, 3.9 Hz, 1H),2.88-2.69 (m, 2H), 2.18-2.06 (m, 4H), 1.95-1.82 (m, 1H), 1.33/1.31 (2 d,J=2.3/2.3 Hx, 3H), 1.01/0.99 (2 s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ:209.9, 155.4, 149.8, 147.1, 141.9, 130.4/129.9, 128.5, 128.4, 125.8,121.2, 116.9, 111.9, 74.8, 58.1/57.3, 55.9, 54.6/54.3, 52.6, 50.2/50.1,48.6/48.2, 38.1, 31.8, 26.6, 19.9, 17.7.

INTERMEDIATE 40Trans-(±)-3-Acetyl-4-(4-methoxy-3-phenethyloxyphenyl)-3-methylpyrrolidine-1-carboxylicAcid Methyl Ester

Prepared by the Mitsunobu procedure of Intermediate 2 from Intermediate37 and 2-phenylethanol.

¹H NMR (300 MHz, CDCl₃) δ: 7.36-7.23 (m, 5H), 6.82 (d, J=8.2 Hz, 1H),6.70 (d, J=8.4 Hz, 1H), 6.66 (s, 1H), 4.18 (t, J=7.5 Hz, 2H), 3.92-3.81(m, 1H), 3.86 (s, 3H), 3.76-3.61 (m, 3H), 3.73 (s, 3H), 3.40/3.27 (2 d,J=11.2/10.9 Hz, 1H), 3.15 (t, J=7.5 Hz, 2H), 2.16/2.12 (2 s, 3H), 1.00(s, 3H).

INTERMEDIATE 41Trans-3-Acetyl-4-[4-methoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-3-methylpyrrolidine-1-carboxylicAcid Methyl Ester

Prepared by the Mitsunobu procedure of Intermediate 2 from Intermediate37 and 3-hydroxytetrahydrofuran.

¹H NMR (300 MHz, CDCl₃) δ: 6.85-6.63 (m, 3H), 4.92-4.88 (m, 1H),4.07-3.62 (m, 8H), 3.84 (s, 3H), 3.75 (s, 3H), 3.39/3.29 (2 d,J=11.2/10.2 Hz, 1H), 2.19-2.14 (m, 5H), 1.02 (br s, 3H). ¹³C NMR (75MHz, CDCl₃) δ: 210.0/209.9, 155.4, 149.5, 146.5, 130.0, 121.6/121.5,116.5/116.4/116.3, 112.0, 111.0, 78.9, 73.0, 67.2, 58.1/57.3, 55.9,54.7/54.3, 52.6, 50.1/50.0, 48.4/48.0, 33.0, 26.6, 17.8.

INTERMEDIATE 42(4R)-3-{[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidin-3-yl]carbonyl}-4-phenyl-1,3-oxazolidin-2-one

To a cooled (−4° C.), stirred slurry of acyl oxazolidinone (9.30 g, 22.8mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (11.7mL, 45.6 mmol, 2 eq.) in CHCl₃ (65 mL) was added a solution of TFA inCHCl₃ (4.6 mL of 1.0 M, 4.6 mmol, 0.2 eq.) via syringe under a nitrogenatmosphere. The resulting slurry was stirred at about 0° C. for 4 hours,then at about 15° C. overnight (water bath). The resulting cloudysolution then was recooled to −4° C., treated with an additional portionof N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (5.9 mL, 22.8mmol, 1 eq.) via syringe, and allowed to stir for 5 hours more duringwhich time the reaction became homogenous. TLC (5% Et₂O in CH₂Cl₂)showed the reaction was complete. The bulk of the CHCl₃ was removed atreduced pressure, and the residue was diluted with EtOAc (250 mL) andwashed successively with 1 N aqueous HCl (2×50 mL), 1 N aqueous NaOH (50mL) and brine (50 mL). The organic layer then was dried (MgSO₄),filtered and concentrated in vacuo to give an orange semi-solid (13.9g). Purification via flash chromatography on silica gel (2% ether inCH₂Cl₂) provided the major diastereomer as a white foam (8.25 g, 65%).

Diastereomeric selectivity about 10:1 (HPLC). ¹H NMR (400 MHz, CDCl₃) δ:7.42-7.21 (c, 10H), 6.95 (s, 1H), 6.81 (s, 2H), 5.55 (dd, 1H), 4.74 (t,1H), 4.68 (m, 1H), 4.10 (dd, 1H), 3.93 (t, 1H), 3.70 (d, 1H), 3.68 (s,3H), 3.56 (d, 1H), 3.42 (d, 1H), 2.72 (m, 2H), 2.64 (d, 1H), 2.48 (m,1H), 1.85-1.78 (c, 2H), 1.75-1.61 (c, 4H), 1.57-1.53 (c, 2H), 0.96 (s,3H). LRMS (Electrospray, positive): Da/e 555.2 (m+1).

INTERMEDIATE 43(3S,4S)-1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidine-3-carboxylicAcid

A suspension of lithium peroxide (0.5 g, 10.8 mmol) in water-THF (1:1, 6mL) was added to a solution of Intermediate 42 (3.0 g, 5.4 mmol) inwater-THF (3:1, 30 mL) at 0° C. under a nitrogen blanket. The suspensionsolubilized immediately. After 1 hour of stirring at 0° C., an aqueoussodium sulfite (Na₂SO₃) solution (1.5 N, 12 mL) was added to quenchexcess peroxide, and THF was removed under reduced pressure. The basicresidue was extracted with three 30 mL portions of CH₂Cl₂. The aqueousphase was acidified to pH 1 with aqueous 1.0 N HCl solution, andextracted with three 30 mL portions of Et₂O. The ether extracts weredried (Na₂SO₄), concentrated under reduced pressure and used withoutfurther purification.

¹H NMR (300 MHz, CDCl₃) δ: 10.73 (br. s, 1H, COOH), 7.69 (br. s, 2H,aromatic), 7.38-7.36 (m, 3H, aromatic), 6.78 (s, 1H, aromatic), 6.69 (m,2H, aromatic), 4.71 (br. s, 1H), 4.51-4.48 (m, 2H), 4.24-4.11 (br. s,2H), 4.08-3.88 (br. s, 1H), 3.76 (s, 3H, OCH₃), 3.54 (br. s, 1H), 3.1(br. s, 1H), 1.83-1.52 (m, 8H, cyclopentyl), 1.05 (br. s, 3H, CH₃).

INTERMEDIATE 44(3S,4S)-1-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-3-methylpyrrolidine-3-carboxylicAcid Methoxy Methyl Amide

Intermediate 44 was prepared from Intermediate 43 (2.1 g, 4.98 mmol),1,1′-carbonyldiimidazole (0.89 g, 5.47 mmol), andN,O-dimethylhydroxylamine hydrochloride (0.73 g, 7.47 mmol) to provideIntermediate 44 (0.9 g, 40%) as a white crystalline powder.

¹H NMR (300 MHz, CDCl₃) δ: 7.4-7.3 (m, 5H, aromatic), 7.06 (d, 1H, J=1.7Hz, aromatic), 6.89 (dd, 1H, J=8.3 Hz, aromatic), 6.73 (d, 1H, J=8.3 Hz,aromatic), 4.77-4.75 (m, 1H), 4.16-4.06(m, 1H), 3.81 (s, 3H, OCH₃),3.81-3.71 (m, 2H), 3.60 (s, 3H, OCH₃) 3.21 (s, 3H, NCH₃), 2.96 (d, 1H,J=9.6 Hz,), 2.91 (m, 1H), 2.78 (d, 1H, J=9.6 Hz,), 2.77 (m, 1H), 2.04(s, 3H, CH₃), 1.92-1.59 (m, 8H, cyclopentyl), 0.94 (s, 3H, CH₃).

INTERMEDIATE 451-[(3S,4S)-1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]ethanone

A solution of Intermediate 44 (0.17 g, 0.43 mmol) in THF (8 mL) wascooled to −78° C. and treated with methyllithium (1.5 M in THF, 0.315mL, 0.47 mmol) under a nitrogen blanket. The solution was stirred for 40minutes at −78° C., then quenched with a cold saturated aqueous NH₄C1solution (8 mL). A mixture of hexanes/CH₂Cl₂ (3:1, 8 mL) was added withvigorous stirring. After a further dilution with more hexanes/CH₂Cl₂(3:1, 10 mL), brine (10 mL) was added and the two layers separated. Theaqueous layer was washed with CH₂Cl₂ (8 mL) and the combined organicextracts washed with brine, dried (Na₂SO₄), filtered, and concentratedunder reduced pressure into an oil product (154 mg, 89%).

¹H NMR (300 MHz, CDCl₃) δ: 7.39-7.24 (m, 5H, aromatic), 6.82-6.70 (m,3H, aromatic), 4.74 (br. s, 1H), 3.81 (s, 3H, OCH₃), 3.78-3.58 (m, 3H),3.14 (d, 1H, J=9.7 Hz ), 3.05 (m, 1H), 2.84 (m, 1H), 2.40 (d, 1H, J=9.7Hz,), 2.23 (s, 3H, CH₃) 1.92-1.59 (m, 8H, cyclopentyl), 0.83 (s, 3H,CH₃).

INTERMEDIATE 46(3S,4S)-3-Acetyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidine-1-carboxylicAcid Methyl Ester

To a stirred solution of Intermediate 45 (0.154 g, 0.38 mmol) inanhydrous acetonitrile (10 mL) was added methyl chloroformate (0.146 mL,1.89 mmol). The solution was heated to 80° C. and refluxed for 3 hours.The solution then was cooled to room temperature, and concentrated underreduced pressure. Purification by reversed-phase HPLC providedIntermediate 46 as an oil (93 mg, 65%). Specific rotation: [α]₂₅₉²³=+2.5 (c=1.0, EtOH).

¹H NMR (300 MHz, CDCl₃) δ: 6.8 (d, 1H, J=8.0 Hz, aromatic), 6.66 (d, 1H,J=8.0 Hz, aromatic), 6.66 (s, 1H, aromatic), 4.73(s, 1H), 3.95-3.64 (m,4H), 3.83 (s, 3H, OCH₃), 3.74 (s, 3H, OCH₃), 3.37 and 3.27(s, 3H, CH₃),2.17 and 2.14 (s, 3H, CH₃), 1.92-1.59 (m, 8H, cyclopentyl), 1.03 and1.02 (s, 3H, CH₃).

INTERMEDIATE 47(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidine-3-carbaldehyde

General Oxazolidinone Reduction/Oxidation Procedure

To a cooled (−78° C.), stirred solution of Intermediate 42 (15.09 g,27.2 mmol) in toluene (250 mL) was added a solution of lithium aluminumhydride in tetrahydrofuran (16.3 mL of 1.0 M, 16.3 mmol, 0.6 eq.) viasyringe under a nitrogen atmosphere. Vigorous bubbling was observed. Theresulting solution was allowed to stir at −78° C. for 2 hours, afterwhich time the cooling bath was removed. The reaction was quenched withthe successive addition of water (0.62 mL), 15% aqueous NaOH (0.62 mL),and water (1.9 mL). The resulting mixture was allowed to warm to roomtemperature, stirred for 30 minutes, then diluted with Et₂O (500 mL) anddried (MgSO₄). Filtration and concentration in vacuo provided thealcohol (with some aldehyde present) as a semi-solid (14.8 g). Thismaterial was used immediately with out further purification.

To a cooled (−78° C.), stirred solution of oxalyl chloride in CH₂Cl₂(10.9 mL of 2.0 M, 21.8 mmol, 0.8 eq.) in more CH₂Cl₂ (75 mL) was addedDMSO (3.1 mL, 43.5 mmol, 1.6 eq.) via syringe under nitrogen atmosphere.After stirring at −78° C. for 20 minutes, a solution of the crudealcohol in CH₂Cl₂ (75 mL) was added by cannula. The resulting yellowsolution was allowed to stir at −78° C. for 20 minutes, then Et₃N (15.2mL, 109 mmol, 4 eq.) was added by syringe. The reaction was allowed tostir at −78° C. for 20 minutes, then warmed to room temperature andstirred for an additional 1 hour. The reaction was quenched with theaddition of brine (150 mL), then extracted with CH₂Cl₂ (2×100 mL).Combined organic layers were dried (MgSO₄), filtered and concentrated invacuo to provide the crude aldehyde. Purification by flash silica gelchromatography (25% EtOAc in hexanes) provided the aldehyde as a clear,colorless oil (9.8 g, 92%).

¹H NMR (400 MHz, CDCl₃) δ: 9.64 (s, 1H), 7.37-7.26 (c, 5H), 6.78-6.76(c, 2H), 6.70 (m, 1H), 4.74 (m, 1H), 3.82 (s, 3H), 3.70 (m, 1H),3.64-3.62 (c, 2H), 3.18-3.13 (c, 2H), 2.84 (t, 1H), 2.41 (d, 1H),1.94-1.83 (c, 6H), 1.63-1.59 (c, 2H), 0.74 (s, 3H). LRMS (Electrospray,positive): Da/e 394.3 (m+1).

INTERMEDIATE 48(4R)-3-{[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxy-phenyl)-3-methyl-1-benzylpyrrolidin-3-yl]carbonyl}-4-phenyl-1,3-oxazolidin-2-one

Prepared via the azomethine cycloaddition procedure of Intermediate 23from Intermediate 17.

¹H NMR (400 MHz, CDCl₃) δ: 7.45-7.12 (m, 15H), 6.95 (d, 1H), 6.78 (d,1H), 5.54 (dd, 1H), 5.17 (c, 1H), 4.69 (t, 1H), 4.22 (dd, 1H), 4.11 (t,1H), 3.84-3.60 (m, 5H), 3.51 (d, 1H), 3.37 (dt, 2H), 3.21 (dd, 2H), 2.90(d, 1H), 2.85 (dd, 1H), 2.76 (dd, 1H), 1.12 (s, 3H).

INTERMEDIATE 49(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidine-3-carbaldehyde

Prepared from Intermediate 48 via the reduction/oxidation procedure ofIntermediate 47.

¹H NMR (400 MHz, CDCl₃) δ: 9.65 (s, 1H), 7.36-7.17 (m, 9H), 6.84 (d,1H), 6.79 (d, 1H), 6.76 (dd, 1H), 5.16 (c, 1H), 3.79 (s, 3H), 3.76 (d,1H), 3.68-3.63 (c, 1H), 3.40-3.31 (m, 2H), 3.24-3.13 (m, 2H), 2.85 (dd,1H), 2.43 (d, 1H), 0.77 (s, 3H).

INTERMEDIATE 50(1R)-1-[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidin-3-yl]ethan-1-ol

Desired, more polar diastereomer. Prepared via the Grignard additionprocedure of Intermediate 56 from Intermediate 49.

¹H NMR (400 MHz, CDCl₃) δ: 7.39-7.17 (m, 9H), 6.84-6.77 (m, 3H), 5.17(c, 1H), 3.80 (s, 3H), 3.72-3.57 (m, 4H), 3.38-3.19 (m, 5H), 3.11 (d,1H), 2.57 (t, 1H), 2.12 (d, 1H), 1.15 (d, 3H), 0.51 (s, 3H).

INTERMEDIATE 51(1R)-1-[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]ethan-1-ol

Prepared via the debenzylation procedure of Intermediate 31 fromIntermediate 50.

¹H NMR (400 MHz, CDCl₃) δ: 7.26-7.16 (m, 4H), 6.81 (s, 3H), 5.19 (c,1H), 3.80 (s, 3H), 3.74-3.68 (m, 2H), 3.44-3.17 (m, 8H), 2.66 (d, 1H),2.51 (br s, 1H), 1.18 (d, 3H), 0.63 (s, 3H).

INTERMEDIATE 52(4R)-3-({(3S,4S)-4-[4-Methoxy-3-(phenylmethoxy)-phenyl]-3-methyl-1-benzylpyrrolidin-3-yl}carbonyl)-4-phenyl-1,3-oxazolidin-2-one(Major Diastereomer)

Prepared via the cycloaddition procedure of Intermediate 23 fromIntermediate 21.

¹H NMR (400 MHz, CDCl₃) δ: 7.49-7.23 (m, 15H), 7.09 (d, 1H), 6.94 (dd,1H), 6.80 (d, 1H), 5.49 (dd, 1H), 5.17 (s, 2H), 4.66 (t, 1H), 4.19 (dd,1H), 4.09 (t, 1H), 3.87 (s, 3H), 3.68 (q, 2H), 3.51 (d, 1H), 2.85-2.79(m, 2H), 2.69 (dd, 1H), 0.99 (s, 3H).

INTERMEDIATE 53(3S,4S)-4-(4-Methoxy-3-(phenylmethoxy)phenyl)-3-methyl-1-benzylpyrrolidine-3-carbaldehyde

Prepared via the reduction/oxidation procedure of Intermediate 47 fromIntermediate 52.

¹H NMR (400 MHz, CDCl₃) δ: 9.56 (s, 1H), 7.43-7.22 (m, 10H), 6.79 (d,1H), 6.77 (d, 1H), 6.71 (dd, 1H), 5.14 (dd, 2H), 3.86 (s, 3H), 3.71 (d,1H), 3.62 (d, 1H), 3.57 (d, 1H), 3.13-3.08 (m, 2H), 2.73 (dd, 1H), 2.30(d, 1H), 0.58 (s, 3H). LRMS (Electrospray, positive): m/z 416.3 (m+1).

INTERMEDIATE 543-[1-Benzyl-4-S-(3-tert-butoxy-4-methoxyphenyl)-3-S-methylpyrrolidine-3-carbonyl]-4-R-phenyl-oxazolidin-2-one

To a stirred solution of Intermediate 22 (39.8 gm, 97 mmol) in CHCl₃(292 mL) at 0° C. under a nitrogen blanket was addedN-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (49.5 mL, 194mmol) followed by TFA acid (1M in CHCl₃, 9.7 mL, 9.7 mmol). The slurrywas allowed to warm to room temperature overnight. TLC in 2/3EtOAc/hexane indicated partial conversion of starting material to aslightly higher R_(f) product. The resultant solution was treated withmore N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (25 mL, 97mmol) to consume residual starting material. After 3 hours at roomtemperature, the reaction appeared complete by TLC. The solution wasconcentrated by rotory evaporator, then redissolved in EtOAc (500 mL).The organics were washed with 2N HCl (2×500 mL), 1N NaOH (2×500 mL), andsaturated NaCl (1×500 mL). The organics were dried (MgSO₄), filtered,and concentrated in vacuo to give Intermediate 54 as an appoximately12:1 ratio of diastereomers. Chromatography on a 110 mm×8″ column with1/3 EtOAc/hexane provided, after concentration in vacuo of pooledfractions, Intermediate 54 (40 gm, 76%) as a yellow foam.

¹H-NMR (CDCl₃, 400 MHz) δ: 7.42-7.20 (m, 10H), 7.11 (s, 1H), 7.05 (d,1H), 6.76 (d, 1H), 5.53 (dd, 1H), 4.65 (dd, 1H), 4.20 (dd, 1H), 4.08(dd, 1H), 3.77 (s, 3H), 3.65 (dd, 2H), 3.51 (d, 1H), 2.82 (dd, 1H), 2.81(d, 1H), 2.71 (dd, 1H), 1.34 (s, 9H), 1.06 (s, 3H).

INTERMEDIATE 55(3R)-4-[3-(tert-Butoxy)-4-methoxyphenyl]-3-methyl-1-benzylpyrrolidine-3-carbaldehyde

To a stirred solution of Intermediate 54 (21.5 gm, 39.7 mmol) in toluene(400 mL) at −78° C. under a nitrogen blanket was added lithium aluminumhydride (1M in THF, 24 mL, 24 mmol) dropwise by syringe over 10 minutes.After 15 minutes, TLC in 4/1 CH₂Cl₂/Et₂O showed complete consumption ofstarting material and appearance of a lower R_(f) material. Methanol (4mL) in toluene (40 mL) was added carefully by syringe at −78° C. withgas evolution. When gas evolution ceased, the reaction was allowed towarm to room temperature, then treated with water (1 mL), 3N NaOH (2mL), and water (1 mL) sequentially. After 10 minutes, the reaction wasdiluted with Et₂O (300 mL) and stirred for 15 minutes. Magnesium sulfatewas added and the mixture filtered through GF/F filter paper with Et₂O.The crude product was concentrated in vacuo and appeared by ¹H-NMR to bean approximately 4:1 mixture of desired aldehyde over reduced alcohol.The crude product was dissolved in CH₂Cl₂ (40 mL). Separately, oxalylchloride (2M in CH₂Cl₂, 11.2 mL, 22.4 mmol) was stirred at −60° C. undera nitrogen blanket and treated with DMSO (3.1 mL, 44 mmol) in CH₂Cl₂ (15mL) dropwise by syringe. After 5 minutes, the aldehyde/alcohol mixturesolution was added to the oxalyl chloride/DMSO solution by cannula. Thereaction was stirred at −60° C. for 45 minutes, then treated with Et₃N(13.8 mL, 100 mmol) and allowed to warm to room temperature. Thesolution was diluted to 200 mL with CH₂Cl₂ and washed with water (1×200mL), 2N HCl (2×200 mL), saturated NaHCO₃ (2×200 mL), and saturated NaCl(1×200 mL). The organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo to a yellow oil which was dissolved in 3/1hexane/EtOAc. After dissolution, the cleaved phenyl oxazolidinoneprecipitated and was removed by filtration. The filtrate waschromatographed on a 70 mm×8″ column with 3/1 hexane/EtOAc to provide(after concentration of product containing fractions in vacuo) pureIntermediate 55 as a yellow oil (13.7 gm, 90%).

¹H-NMR (400 MHz, CDCl₁) δ: 9.62 (s, 1H), 7.37-7.22 (m, 5H), 6.92 (s,1H), 6.84 (d, 1H), 6.79 (d, 1H) 3.79 (s, 3H), 3.71 (dd, 2H) 3.62 (dd,1H), 3.17 (dd, 1H), 2.80 (dd, 1H), 2.38 (d, 1H), 1.35 (s, 9H), 0.73 (s,3H).

INTERMEDIATES 56(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-methyl-1-benzylpyrrolidin-3-yl]ethan-1-ol

Grignard Addition Procedure

To a cooled (0° C.), stirred solution of Intermediate 47 (0.96 mg, 2.45mmol) in dry Et₂O (10mL) was added a solution of methylmagnesium iodide(or other Grignard reagent) in ether (2.45 mL of 3.0 M, 7.35 mmol, 3eq.) via syringe under a nitrogen atmosphere. After stirring at 0° C.for 15 minutes, the reaction was allowed to warm to room temperature andstirred for 2 hours. The reaction then was carefully quenched withsaturated aqueous NH₄Cl (40 mL), and extracted with EtOAc (3×50 mL).Combined organic layers were washed with brine, dried (Na₂SO₄) filtered,and concentrated in vacuo to give 990 mg of an orange oil. Purificationvia flash silica gel chromatography (CH₂Cl₂ to 5% methanol in CH₂Cl₂)afforded the less polar diastereomer (419 mg, 42%) and the more polardiastereomer (375 mg, 37%) as colorless, viscous oils.

Less Polar Diastereomer:

(1S)-1-[(3S,4S)-4-(3-cyclopentyloxy-4-methoxy-phenyl)-3-methyl-1-benzylpyrrolidin-3-yl]ethan-1-ol

¹H NMR (400 MHz, CDCl₃) δ: 7.34-7.28 (c, 5H), 6.79-6.73 (c, 3H), 4.74(m, 1H), 3.82 (s, 3H), 3.74 (q, 1H), 3.65 (q, 2H), 3.53 (t, 1H), 3.40(t, 1H), 2.99 (d, 1H), 2.50 (t, 1H), 2.35 (d, 1H), 1.94-1.81 (c, 6H),1.63-1.59 (c, 2H), 1.10 (d, 3H), 0.52 (s, 3H). LRMS (Electrospray,positive): Da/e 410.3 (m+1).

More Polar Diastereomer:

(1R)-1-[(3S,4S)-4-(3Cyclopentyloxy-4-methoxy-phenyl)-3-methyl-1-benzylpyrrolidin-3-yl]ethan-1-ol

¹H NMR (400 MHz, CDCl₃) δ: 7.33-7.31 (c, 5H), 6.79-6.72 (c, 3H), 4.74(m, 1H), 3.82 (s, 3H), 3.69-3.56 (c, 4H), 3.29 (t, 1H), 3.10 (d, 1H),2.56 (t, 1H), 2.09 (d, 1H), 2.04 (s, 3H), 1.92-1.81 (c, 6H), 1.62-1.59(c, 2H), 1.13 (d, 3H), 0.47 (s, 3H). LRMS (Electrospray, positive): Da/e410.3 (m+1).

INTERMEDIATE 57(1S)-1-{(3S,4S)-4-[4-Methoxy-3-(phenylmethoxy)-phenyl]-3-methyl-1-benzylpyrrolidin-3-yl}ethan-1-ol

Less polar diastereomer. Prepared via the Grignard procedure ofIntermediate 56 from Intermediate 53.

¹H NMR (400 MHz, CDCl₃) δ: 7.44-7.22 (m, 10H), 6.80 (d, 1H), 6.75 (dd,1H), 6.67 (d, 1H), 5.17 (s, 2H), 3.88 (s, 3H), 3.66 (q, 1H), 3.60 (d,2H), 3.43 (t, 1H), 2.92 (d, 1H), 2.38 (t, 1H), 2.22 (d, 1H), 0.98 (d,3H), 0.32 (s, 3H). LRMS (Electrospray, positive): m/z 432.5 (m+1).

INTERMEDIATE 58(1R)-1-{(3S,4S)-4-[4-Methoxy-3-(phenylmethoxy)-phenyl]-3-methyl-1-benzylpyrrolidin-3-yl}ethan-1-ol

More polar, desired diastereomer. Prepared via the Grignard procedure ofIntermediate 56 from Intermediate 53.

¹H NMR (400 MHz, CDCl₃) δ: 7.43-7.21 (m, 10H), 6.79 (d, 1H), 6.75-6.70(m, 2H), 5.16 (dd, 2H), 3.87 (s, 3H), 3.64-3.49 (m, 4H), 3.23 (t, 1H),3.06 (d, 1H), 2.46 (t, 1H), 1.99 (d, 1H), 1.07 (d, 3H), 0.28 (s, 3H).LRMS (Electrospray, positive): m/z 432.5 (m+1).

INTERMEDIATE 591-R-[1-Benzyl-4-S-(3-tert-butoxy-4-methoxyphenyl)-3-S-methylpyrrolidin-3-yl]ethanol

To a stirred solution of trimethylaluminum (2M in toluene, 59.4 mL, 119mmol) at 0° C. under a nitrogen blanket was added methylmagnesium iodide(3M in Et₂O, 36 mL, 108 mmol). After 30 minutes at 0° C., theorganometallic solution was added via cannulation to a solution ofIntermediate 55 (13.7 gm, 36 mmol) in CH₂Cl₂ (360 mL) at −78° C. under anitrogen blanket. After complete addition, the reaction was stirred at−73° C. for 6 hours. The reaction then was warmed to 0° C. and carefullypoured into ice cold 1M potassium sodium tartrate (1500 mL) with rapidstirring, and diluted with EtOAc (1500 mL). After stirring for 15minutes, the layers were separated and the organics washed with 1Mpotassium sodium tartrate (1×1000 mL) and saturated NaCl (1×1000 mL).The organics were dried (MgSO₁), filtered, and concentrated in vacuo toprovide a 2.5:1 mixture of diastereomers plus approximately 10% residualstarting aldehyde by crude ¹H-NMR. The crude product was chromatographedon a 110 mm×8″ column with 3/7/0.4 EtOAc/hexane/-MeOH to provide, afterpooling and concentration in vacuo of the desired lower R₅ diastereomercontaining fractions, Intermediate 59 (8.1 gm, 57%) as an orange oil.

¹H-NMR (CDCl₃, 400 MHz) δ: 7.34-7.23 (m, 5H), 6.86 (m, 3H), 6.79 (d,1H), 3.79 (s, 3H), 3.65 (dd, 1H), 3.62 (s, 2H), 3.58 (dd, 1H), 3.29 (dd,1H), 3.10 (d, 1H), 2.53 (dd, 1H), 2.07 (d, 1H), 1.35 (s, 9H), 1.12 (d,3H), 0.45 (s, 3H).

INTERMEDIATE 603-(3-Cyclopropylmethoxy-4-methoxyphenyl)-2-methyl-E-acrylic Acid EthylEster

A round-bottomed flash was charged with THF (850 mL) and triethyl2-phosphonopropionate (97.2 g, 0.408 mol) and the resulting mixture wascooled to 0° C. Lithium hexamethyldisilazide (1.0 M in THF, 489 mL,0.489 mol) then was added dropwise. The mixture was stirred for 30minutes at 0° C., then a solution of Intermediate 1 (70 g, 0.34 mol) inTHF (100 mL) was added. After the dropwise addition, the reactionmixture was maintained at 22° C. for 62 hours. The reaction was quenchedwith saturated NaCl and diluted with EtOAc. After separation, theorganic layer was washed with saturated NaCl, dried over Na₂SO₄, andconcentrated in vacuo. The green oil was purified by chromatographythrough a pad of SiO2 (650 g) using EtOAc/hexanes (1:10) as eluant,(40.8 g).

¹H NMR (400 MHz, CDCl₃) δ: 7.67-7.61 (m, 1H), 7.07-7.02 (m, 1H),6.98-6.95 (m, 1H), 6.92-6.89 (m, 1H), 4.32-4.25 (m, 2H), 3.92 (s, 3H),3.90-3.85 (m, 2H), 2.15 (s, 3H), 1.38-1.32 (m, 4H), 0.70-0.63 (m, 2H),0.41-0.37 (m, 2H).

INTERMEDIATE 613-(3-Cyclopropylmethoxy-4-methoxy-phenyl)-2-methyl-E-acrylic Acid

Intermediate 60 (26.9 g, 93 mmol) was dissolved in 1,4-dioxane (95 mL)and treated with a solution of LiOH monohydrate (4.6 g, 111 mmol)dissolved in water (95 mL). The resulting solution was heated at 80° C.for 3 hours, then stirred overnight at room temperature. The reactionmixture was poured into water (350 mL) and extracted twice with Et₂O(500 mL total). The aqueous layer was diluted with EtOAc (350 mL) andthe pH was adjusted with concentrated H₃PO₄ (24 mL). The layers wereseparated, the EtOAc layer was washed with water and saturated NaCl,dried over MgSO₄, and concentrated in vacuo (20.4 g).

¹H NMR (400 MHz, CDCl₃) δ: 7.77 (s, 1H), 7.11-7.07 (dd, 1H), 7.02-6.98(d, 1H), 6.93-6.90 (d, 1H), 3.93 (s, 3H), 3.86 (d, 2H), 2.18 (s, 3H),1.39-1.31 (m, 1H), 0.69-0.63 (m, 2H), 0.39-0.35 (m, 2H).

INTERMEDIATE 623-(3-Cyclopropylmethoxy-4-methoxyphenyl)-2-methyl-E-acryloyl Chloride

Intermediate 61 (55.8 g, 0.213 mol) was dissolved in CH₂Cl₂ (300 mL) andcooled to 0° C. with a drying tube attached. Oxalyl chloride (2.0 M inCH₂Cl₂, 117 mL, 0.234 mol) was added followed by addition of DMF (1.0mL). The reaction mixture was maintained at 22° C. for several hours.The mixture was diluted with CH₂Cl₂ and washed with water, saturatedNaCl, then dried over Na₂SO₄, and concentrated in vacuo (65.1 g yellowsolid).

¹H NMR (400 MHz, CDCl₃) δ: 7.97 (s, 1H), 7.16-7.11 (dd, 1H), 7.03-7.00(d, 1H), 6.95-6.91 (dd, 1H), 3.93 (s, 3H), 3.87 (d, 2H), 2.23 (s, 3H),1.39-1.31 (m, 1H), 0.69-0.64 (m, 2H), 0.40-0.37 (m, 2H).

INTERMEDIATE 633-[3-(3-Cyclopropylmethoxy-4-methoxyphenyl)-2-methyl-E-acryloyl]-4-(R)-phenyloxazolidin-2-one

4-(R)-Phenyloxazolidin-2-one (33.0 g, 0.202 mol) was dissolved in THF (1L) and cooled to −78° C. n-Butyl lithium (2.5 M in hexanes, 79.5 mL,0.198 mol) was added, and the resulting reaction mixture was stirred for20 minutes. A solution of Intermediate 62 (65.1 g, 0.213 mol) in THF(200 mL) was added dropwise over 15 minutes. The reaction mixture wasstirred for 1 hour at −78° C., then warmed to 0° C., slowly. Thereaction mixture became thick with beige solids. The mixture wasneutralized at 0° C. with saturated NH₄Cl (600 mL) and water (300 mL).The solution was warmed to 22° C. quickly and poured into CHCl₃ (2400mL). After shaking and separation, the organic layer was washed withwater (1 L), saturated NaCl (1 L), dried over Na₂SO₄, and concentratedin vacuo to a pale orange solid (94.4 g).

¹H NMR (400 MHz, CDCl₃) δ: 7.41-7.32 (m, 5H), 7.07-6.98 (m, 2H),6.95-6.93 (d, 1H), 6.90-6.86 (d, 1H), 5.55-5.51 (dd, 1H), 4.77-4.71 (dd,1H), 4.30-4.26 (dd, 1H), 3.91 (s, 3H), 3.85 (d, 2H), 2.17 (s. 3H),1.38-1.29 (m, 1H), 0.66-0.62 (m, 2H), 0.39-0.34 (m, 2H).

INTERMEDIATE 643-[1-Benzyl-4-(S)-(3-cyclopropylmethoxy-4-methoxy-phenyl)-3-(S)-methylpyrrolidine-3-carbonyl]-4-(R)-phenyloxazolidin-2-one

Intermediate 63 (94.4 g, 0.21 mol) was dissolved in CHCl₃ (640 mL), thencooled to 0° C. Benzyl methoxymethyltrimethylsilanylmethylamine (95 g,0.40 mol) was added, and the reaction mixture was treated dropwise witha solution of TFA (3.08 mL) in CHCl₃ (40 mL). The reaction was stirredovernight while warming to 22° C. Additional benzylmethoxymethyltrimethylsilanylmethylamine (71.2 g, 0.3 mol) was added,then the mixture was stirred for an additional 68 hours. The reactionwas quenched with saturated NH₄Cl (600 mL) and separated. The organiclayer was washed twice with 1 N HCl (500 mL), once with water, once with1 N NaOH (500 mL), once with water, once with 6% NaHCO₃, once withsaturated NaCl, dried over Na₂SO₄, and concentrated in vacuo. The crudematerial was chromatographed on SiO₂ (1.2 kg) in two portions usinghexanes/EtOAc (2:1) as eluant (62.3 g).

¹H NMR (400 MHz, CDCl₃) δ: 7.44-7.20 (m, 10H), 7.07 (d, 1H), 6.94-6.91(dd, 1H), 6.78-6.76 (d, 1H), 5.56-5.50 (dd, 1H), 4.69-4.63 (dd, 1H),4.21-4.16 (dd, 1H), 3.83-3.80 (m, 2H), 3.82 (s, 3H), 3.74-3.70 (d, 1H),3.64-3.59 (d, 1H), 3.50-3.46 (d, 1H), 2.90-2.86 (d, 1H), 2.83-2.71 (m,2H), 1.36-1.29 (m, 1H) 0.64-0.60 (m, 2H), 0.38-0.32 (m, 2H).

INTERMEDIATE 651-Benzyl-4-(S)-(3-cyclopropylmethoxy-4-methoxy-phenyl)-3-(S)-methylpyrrolidine-3-carbaldehyde

Intermediate 64 (62.3 g, 0.115 mol) was dissolved in toluene (1 L), thencooled to −78° C. The solution was treated with lithium aluminum hydride(1.0 M in THF, 69 mL, 69 mmol) by slow addition. The reaction wasstirred for 0.5 hours, then quenched at −78° C. with a dropwise additionof MeOH (13 mL). The reaction was stirred for 5 minutes at −78° C.,warmed to 0° C., followed by an addition of water (2.62 mL), 15% NaOH(2.62 mL), and water (7.85 mL). The solution was stirred for 10 minutes,then Et₂O was added (1.5 L) and the resulting mixture was stirredovernight at 22° C. Magnesium sulfate was added and after stirring for15 minutes, the solution was filtered through MgSO₄ and concentrated invacuo. NMR showed that the products of this reaction were a mixture ofthe desired aldehyde and the primary alcohol (about 4:1). This materialwas used without further purification in the following Swern oxidationbelow. Oxalyl chloride (2.0 M in CH₂Cl₂, 25 mL, 50 mmol) was added toCH₂Cl₂ (75 mL) and cooled to −60° C. Dimethylsulfoxide (7.1 mL, 100mmol) was added as a solution in CH₂Cl₂ (30 mL) in a dropwise manner.After 5 minutes, a solution of aldehyde/alcohol mixture (4:1, ˜0.115mol, (ca. 0.05 mol alcohol)) dissolved in CH₂Cl₂ was added dropwise. Themixture was stirred for 30 minutes, then Et₃N (31 mL, 222 mmol) wasadded, and the solution was warmed to 22° C. and stirred overnight. Thereaction was quenched with water and stirred vigorously for 20 minutes,then separated. The aqueous layer was washed with CH₂Cl₂. The combinedorganic layers were washed with saturated NaCl, dried over Na₂SO₄, andconcentrated in vacuo. Intermediate 65 was purified by filterchromatography using hexanes/EtOAc (4;1) as eluant (42 g).

¹H NMR (400 MHz, CDCl₃) δ: 9.64 (s, 1H), 7.39-7.23 (m, 5H), 6.81-6.71(m, 3H), 3.83 (s, 3H), 3.33-3.31 (m, 2H), 3.80-3.75 (d, 1H), 3.67-3.61(m, 2H), 3.19-3.11 (m, 2H), 2.86-2.81 (m, 1H), 2.43-2.40 (m, 1H),1.38-1.29 (m, 1H), 0.76 (s, 3H), 0.68-0.62 (m, 2H), 0.30-0.37 (m, 2H).

INTERMEDIATE 661-[1-Benzyl-4-(S)-(3-cyclopropylmethoxy-4-methoxy-phenyl)-3-(S)-methylpyrrolidin-3-yl]ethanol

Trimethylaluminum (2.0 M in toluene, 2.1 mL, 4.2 mmol) was cooled to 0°C. and methylmagnesium iodide (3.0 M in ethyl ether, 1.3 mL, 3.95 mmol)was added dropwise. This grey suspension was stirred at 0° C. for 30minutes then it was added through a cannula to a solution ofIntermediate 65 (0.5 g, 1.3 mmol) dissolved in CH₂Cl₂ (6.6 mL), whichwas cooled to −78° C. The reaction mixture was stirred at −78° C. for 6hours. The mixture then was poured directly into a separatory funnelcontaining Rochelle's salt (1 M, 150 mL). The residue was rinsed intothe funnel with EtOAc. The mixture was diluted with EtOAc and separated.The organic layer was washed a second time with Rochelle's salt,followed by saturated NaCl, dried over MgSO₄, and concentrated in vacuo.The crude product was a mixture (1:1) of the two diasteromeric alcoholsplus a small amount of aldehyde. These materials were separable bychromatography on SiO₄ with EtOAc/hexanes (1:1). Desired more polarcarbinol:

¹H NMR (400 MHz, CDCl₃) δ: 7.36-7.30 (m, 3H), 7.28-7.24 (m, 2H),6.81-6.74 (m, 3H), 3.85 (s, 3H), 3.84-3.79 (m, 2H), 3.71-3.56 (m, 4H),3.33-3.25 (dd, 1H), 3.12-3.09 (d, 1H), 2.59-2.53 (dd, 1H), 2.16-2.08 (d,1H), 1.38-1.25 (m, 1H), 1.16 (d, 3H), 0.69-0.61 (m, 2H), 0.49 (s, 3H),0.39-0.35 (m, 2H).

INTERMEDIATE 67(1R)-1-{(3S,4S)-4-[3-(Cyclopropylmethoxy)-4-methoxy-phenyl]-3-methylpyrrolidin-3-yl}ethan-1-ol

Prepared from Intermediate 66 by the debenzylation procedure ofIntermediate 31.

¹H NMR (400 MHz, CDCl₃) δ: 6.88-6.71 (m, 3H), 3.92-3.56 (c, 11H),3.14-3.05 (m, 1H), 1.37-1.25 (m, 1H), 1.20 (d, 2H), 0.72 (s, 3H), 0.63(d, 2H), 0.37 (d, 2H). LRMS (Electrospray, positive): Da/e 306.2 (m+1).

INTERMEDIATE 68(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-methylpyrrolidin-3-yl]ethan-1-ol

Prepared by the debenzylation procedure of Intermediate 31 from the1-(R) carbinol isomer (more polar diastereomer) of Intermediate 56.

¹H NMR (400 MHz, CDCl₃) δ: 6.81 (d, 1H), 6.75-6.73 (m, 2H), 4.80 (c,1H), 3.82 (s, 3H), 3.79-3.68 (m, 5H), 3.61 (t, 1H), 3.10 (d, 1H),1.96-1.80 (m, 6H) 1.63-1.57 (m, 2H), 1.21 (d, 3H), 0.72 (s, 3H) LRMS(Electrospray, positive): Da/e 320.4 (m+1).

INTERMEDIATE 69(1S)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-methylpyrrolidin-3-yl]ethan-1-ol

Prepared by the debenzylation procedure of Intermediate 31 from the1-(S) isomer (less polar intermediate) of Intermediate 56.

LRMS (Electrospray, positive): Da/e 320.4 (m+1).

INTERMEDIATE 705-[4-((1R)-1-Hydroxyethyl)(3S,4S)-4-methylpyrrolidin-3-yl]-2-methoxyphenolPrepared from Intermediate 58 via the debenzylation procedure ofIntermediate 31 (10% palladium on carbon used in place of palladiumacetate).

¹H NMR (400 MHz, CDCl₃) δ: 6.72 (d, 1H), 6.67 (d, 1H), 6.59 (dd, 1H),3.90 (s, 31), 3.60 (qd, 1H), 3.29-3.17 (m, 6H), 3.10 (t, 1H), 2.55 (d,1H), 1.06 (d, 3H), 0.56 (s, 3H) LRMS (Electrospray, positive): m/z 252.1(m+1).

INTERMEDIATE 711-R-[1-Benzyl-4-S-(3-tert-butoxy-4-methoxyphenyl)-3-S-methylpyrrolidin-3-yl]-ethanol

To a stirred solution of trimethylaluminum (2M in toluene, 59.4 mL, 119mmol) at 0° C. under a nitrogen blanket was added methylmagnesium iodide(3M in Et₂O, 36 mL, 108 mmol). After 30 minutes at 0° C., theorganometallic solution was added via cannula to a solution ofIntermediate 55 (13.7 gm, 36 mmol) in CH₂Cl₂ (360 mL) at −78° C. under anitrogen blanket. After complete addition, the reaction was stirred at−78° C. for 6 hours. The reaction then was warmed to 0° C. and carefullypoured into ice cold 1M potassium sodium tartrate (1500 mL) with rapidstirring, and diluted with EtOAc (1500 mL). After stirring for 15minutes, the layers were separated, and the organic layers washed with1M potassium sodium tartrate (1×1000 mL) and saturated NaCl (1×1000 mL).The organic layers were dried (MgSO₄), filtered, and concentrated invacuo to provide a 2.5:1 mixture of diastereomers plus approximately 10%residual starting aldehyde by crude ¹H-NMR. The crude product waschromatographed on a 110 mm×8″ column with 3/7/0.4 EtOAc/hexane/MeOH toprovide, after pooling and concentration in vacuo of the desired lowerR₅ diastereomer containing fractions, Intermediate 71 (8.1 gm, 57%) asan orange oil.

¹H-NMR (400 MHz, CDCl₃) δ: 7.34-7.23 (m, 5H), 6.86 (m, 3H), 6.79 (d,1H), 3.79 (s, 3H), 3.65 (dd, 1H), 3.62 (s, 2H), 3.58 (dd, 1H), 3.29 (dd,1H), 3.10 (d, 1H), 2.53 (dd, 1H), 2.07 (d, 1H), 1.35 (s, 9H), 1.12 (d,3H), 0.45 (s, 3H).

INTERMEDIATE 725-[(4R)-4-((1S)-1-Hydroxyethyl)-4-methyl-1-benzyl-pyrrolidin-3-yl]-2-methoxyphenol

To a stirred solution of Intermediate 71 (2.3 gm, 5.8 mmol) in CH₂Cl₂(18 mL) at 0° C. under a drying tube was added trifluoroacetic acid (2.7mL, 35 mmol). The cooling bath was removed and the reaction allowed towarm to room temperature, then stirred for 3.5 hours. The reaction wasconcentrated by rotary evaporator to remove excess trifluoroacetic acid,redissolved in CH₂Cl₂ (50 mL), then washed with 10% Na₂CO₃ (2×50 mL) andsaturated NaCl (1×50 mL). The organic layers were dried (MgSO₄),filtered, and concentrated in vacuo to provide Intermediate 72 as awhite foam (1.9 gm, 96%).

¹H-NMR (400 MHz, CDCl₃) δ: 7.36-7.20 (m, 5H), 6.82 (s, 1H), 6.77 (d,1H), 6.66 (d, 1H), 5.57 (s, 1H), 3.83 (s, 3H), 3.70-3.56 (m, 4H), 3.30(dd, 1H), 3.13 (d, 1H), 2.55 (dd, 1H), 2.04 (d, 1H), 1.12 (d, 3H), 0.45(s, 3H).

INTERMEDIATE 73(1R)-1-{(3R)-4-[3-(tert-Butoxy)-4-methoxyphenyl]-3-methylpyrrolidin-3-yl}ethan-1-ol

Prepared from Intermediate 71 (1 gm, 2.53 mmol) by the debenzylationprocedure of Intermediate 31 to give 775 mg of Intermediate 73.

¹H-NMR (400 MHz, CDCl₃) δ: 6.92-5.79 (m, 3H), 3.78 (s, 3H), 3.51-3.42(m, 4H), 3.29 (dd, 1H), 2.77 (d, 1H), 1.35 (s, 9H), 1.17 (d, 3H), 0.62(s, 3H).

INTERMEDIATE 74

R¹=H

Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylate

Hunig's Base Mediated Acylation Procedure

To a cooled (0° C.), stirred solution of Intermediate 70 (670 mg, 2.67mmol) and Hunig's base (1.4 mL, 8.0 mmol) in dry CH₂Cl₂ (10 mL),1,4-dioxane (5 mL), and MeOH (1 mL) was added methyl chioroformate (0.41mL, 5.3 mmol) via syringe under a nitrogen atmosphere. The resultingsolution was allowed to stir at 0° C. for 1 hour, then diluted withCH₂Cl₂ (90 mL), washed successively with 1 N aqueous HCl (2×20 mL) andbrine (20 mL), and dried (Na₂SO₄), filtered, and concentrated in vacuo.The residue (737 mg) was dissolved in THF (3 mL) and water (2 mL), thentreated with a solution of LiOH (112 mg, 2.67 mmol in 2 mL water) atroom temperature. After stirring for 4 hours, the reaction was dilutedwith EtOAc (100 mL) and washed successively with 1 N aqueous HCl (2×50mL), saturated aqueous NaHCO₃ (30 mL), and brine (30 mL), then dried(Na₂SO₄), filtered, and concentrated in vacuo. The residue was purifiedvia radical chromatography (4 mm plate with 3% MeOH In CH₂Cl₂) toprovide Intermediate 74 as a light tan foam (250 mg, 30%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.84 (d 1H), 6.78 (d,1H), 6.72 (dd, 1H), 5.57 (d, 1H) 3.90-3.54 (m, 1H), 3.30 (d, 0.5H), 3.20(d, 0.5H), 1.35 (br d, 1H), 1.14 (t, 3H), 0.75 (s, 3H). LRMS(Electrospray, negative): m/z 308.6 (m−1). LRMS (Electrospray,positive): m/z 310.5 (m+1).

INTERMEDIATE 75

From Intermediate 57 via debenzylation procedure of Intermediate 31 andHunig's Base Mediated Acylation procedure of Intermediate 74. LRMS(Electrospray, negative): m/z 308.6 (m−1). LRMS (Electrospray,positive): m/z 310.5 (m+1).

INTERMEDIATE 76 (2R)-2-Hydroxyhexanoic Acid

To a cooled (0° C.), stirred solution of D-norleucine (500 mg, 3.81mmol) in 10 mL of 1N aqueous sulfuric acid was added sodium nitrite (421mg, 6.10 mmol) in 3 mL of water dropwise over a 20-minute period. Thereaction mixture was allowed to slowly warm to room temperature over a16-hour period. The mixture then was extracted with EtOAc (2×25 mL),dried (Na₂SO₄), and concentrated to yield 200 mg (40%) of a white waxysolid.

¹H NMR (400 MHz, CDCl₃) δ: 4.28 (dd, 1H), 1.92-1.81 (m, 1H), 1.76-1.64(m, 1H), 1.51-1.29 (m, 4H), 0.92 (t, 3H). LRMS (Electrospray, negative):Da/e 131.1 (m−1).

INTERMEDIATE 77 (1R)-1-(Chlorocarbonyl)pentyl Acetate

Acylation/Hydrolysis/Acid Chloride Formation Procedure

To a cooled (0° C.) solution of Intermediate 76 (200 mg, 1.51 mmol) andHunig's base (657 mL, 3.78 mmol) in CH₂Cl₂ (6 mL) was added acetylchloride (215 μL, 3.03 mmol) by syringe. The resulting mixture wasallowed to slowly warm to room temperature over a 16 hour period. Thereaction mixture then was washed with 1N HCl (2×20 mL), dried (Na₂SO₄),and concentrated to an orange brown oil, which by NMR was shown to bethe bis-acylated material. To this material was added 5 mL of 4:1THF:water, and the mixture stirred for 16 hours at room temperature,extracted with EtOAc, dried (Na₂SO₄), and concentrated to 186 mg (71%)of an orange oil. NMR and mass spectrometry confirmed the acetoxy acid.To this material in 5 mL of CH₂Cl₂ was added oxalyl chloride (1.07 mL,2.14 mmol, 2M solution in CH₂Cl₂) and a drop of DMF. The mixture wasstirred at room temperature for 4 hours, then concentrated under reducedpressure to afford Intermediate 77.

¹H NMR (400 MHz, CDCl₃) δ: 5.17 (dd, 1H), 2.13 (s, 3H) 2.04-1.86 (m, 2H)1.50-1.30 (m, 4H), 0.93 (t, 3H).

INTERMEDIATE 78 (Chlorocarbonyl)(4-fluorophenyl)methyl Acetate

Prepared via the acylation/hydrolysis/acid chloride formation procedureof Intermediate 77 from 2-(4-fluorophenyl)-2-hydroxyacetic acid.

¹H NMR (400 MHz, CDCl₃) δ: 7.48 (q, 2H), 7.14 (t, 2H), 6.06 (s, 1H),2.21 (s, 3H).

INTERMEDIATE 79 (Chlorocarbonyl)cyclopropyl Acetate

Prepared via the acylation/hydrolysis/acid chloride formation procedureof Intermediate 77 from 1-hydroxycyclopropanecarboxylic acid.

¹H NMR (400 MHz, CDCl₃) δ: 2.13 (s, 3H), 1.89-1.84 (m, 2H) 1.46-1.42 (m,2H).

INTERMEDIATE 80 (1S)-1-(Chlorocarbonyl)-2-methylbutyl Acetate

Prepared via the acylation/hydrolysis/acid chloride formation procedureof Intermediate 77 from (2S)-2-hydroxy-3-methylpentanoic acid.

¹H NMR (400 MHz, CDCl₃) δ: 5.01 (d, 1H), 2.24-2.17 (m, 1H), 2.17 (s,3H), 1.57-1.47 (m, 1H), 1.39-1.28 (m, 1H), 1.03 (d, 3H), 0.94 (t, 3H).

INTERMEDIATE 81 (1S)-1-(Chlorocarbonyl)-3-mathylbutyl Acetate

Prepared via the acylation/hydrolysis/acid chloride formation procedureof Intermediate 77 from (2S)-2-hydroxy-4-methylpentanoic acid.

¹H NMR (400 MHz, CDCl₃) δ: 5.12 (d, 1H), 2.16 (s, 3H), 1.88-1.75 (m,3H), 0.97 (dd, 6H).

INTERMEDIATE 82 (1R)-1-(Chlorocarbonyl)-2-phenylethyl Acetate

Prepared via the acylation/hydrolysis/acid chloride formation procedureof Intermediate 77 from (2R)-2-hydroxy-3-phenylpropanoic acid.

¹H NMR (400 MHz, CDCl₃) δ: 7.38-7.21 (m, 5H), 5.33 (dd, 1H), 3.33 (dd,1H), 3.18 (dd, 1H), 2.11 (s, 3H).

INTERMEDIATE 83 (1S)-1-(Chlorocarbonyl)-2-phenylethyl Acetate

Prepared via the acylation/hydrolysis/acid chloride formation procedureof Intermediate 77 from (2S)-2-hydroxy-3-phenylpropanoic acid.

¹H NMR (400 MHz, CDCl₃) δ: 7.38-7.21 (m, 5H), 5.33 (dd, 1H), 3.33 (dd,1H), 3.18 (dd, 1H), 2.11 (s, 3H).

INTERMEDIATE 84 (4-Chlorophenyl)(hydroxyimino)methylamine

A solution of 4-chlorobenzonitrile (10 g, 0.073 mole), hydroxylaminehydrochloride, and NaOH (3.5 g, 0.087 mole) in ethanol (300 mL) andwater (80 mL) was refluxed for 10 hours, then concentrated under reducedpressure. The resulting off-white solid was taken up in water/4:1EtOAc:CH₂Cl₂. The organic layers were isolated, washed once with water,dried (Na₂SO₄), and concentrated to 10.4 g of a white solid (84%).

¹H NMR (DMSO-d₅, 400 MHz) δ: 9.71 (s, 1H), 7.66 (d, 2H), 7.41 (d, 2H),5.85 (br s, 2H).

INTERMEDIATE 85 [3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl Acetate

To a chilled (0° C.) solution of Intermediate 84 (4.5 g, 0.026 mole) indry pyridine (20 mL) was added acetoxyacetyl chloride (6 mL, 0.056 mole)dropwise over a one-hour period. After the addition was complete, themixture was heated at 90° C. for three hours, then allowed to cool toroom temperature. The pyridine was removed under reduced pressure, andthe resulting dark oily material was taken up in CH₂Cl₂ and filteredthrough GF/F filter paper. The filtrate was washed with brine (2×100mL), dried (Na₂SO₄), and concentrated. Biotage purification (40Mcartridge, 20% EtOAc/hexane) afforded 1.93 g of Intermediate 85 as awhite solid (29%).

¹H NMR (400 MHz, CDCl₃) δ: 8.01 (d, 2H), 7.46 (d, 2H), 5.35 (s, 2H),2.21 (s, 3H).

INTERMEDIATE 86 [3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]methan-1-ol

To a solution of Intermediate 85 (1 g, 3.96 mmol) in MeOH (50 mL) wasadded aqueous K₂CO₃ (0.56 M, 7 mL, 3.96 mmol) and the mixture stirred atroom temperature for two hours. The solvents then were removed underreduced pressure, and the residue taken up in EtOAc (75 mL), washed withwater (2×75mL), dried (Na₂SO₄), and concentrated to 820 mg (98%) ofIntermediate 86 as a white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.02 (d, 2H), 7.47 (d, 2H), 4.97 (s, 2H),2.52 (br s, 1H).

INTERMEDIATE 87 [3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]methylMethylsulfonate

Prepared via the mesylation procedure of Intermediate 90.

¹H NMR (400 MHz, CDCl₃) δ: 8.02 (d, 2H), 7.47 (d, 2H), 5.49 (s, 2H),3.24 (s, 3H).

INTERMEDIaTE 88 3-[4-(Trifluoromethyl)phenyl]prop-2-yn-1-ol

Palladium Catalyzed Coupling Procedure

A solution of 4-iodobenzotrifluoride (5 g, 0.018 copper (I) iodide (17.5mg, 0.092 mmol), and bis-triphenylphosphinepalladium(II) chloride (129mg, 0.184 7 mmol) in 50 mL, of diethylamine was stirred at roomtemperature for several hours. The diethylamine then was removed underreduced pressure and the residue taken up in CH₂Cl₂ (150 mL). This waswashed with 1N HCl (3×150 mL), dried (Na₂SO₄), and concentrated to 3.1 gof Intermediate 88 as an orange/brown oil (84%).

¹H NMR (400 MHz, CDCl₃) δ: 7.55 (q, 4H), 4.52 (d, 2H), 1.74 (br s, 1H).

INTERMEDIATE 89 3-(4-Florophenyl)prop-2-yn-1-ol

Prepared via the procedure of Intermediate 88.

¹H NMR (400 MHz, CDCl₃) δ: 7.42(q, 2H), 7.01 (t, 2H), 1.70 (t, 1H).

INTERMEDIATE 90 3-Phenylprop-2-ynyl Methylsulfonate

Mesylatioon Procedure

To a solution of 3-phenyl-2-propyn-1-ol (100 g, 0.757 mole) and Et₃N(158 mL, 1.13 mole) in 3 liters of dry CH₂Cl₂ chilled to 5° C. was addedmethanesulfonyl chloride (59 mL, 0.757 mole) via an addition funnel,maintaining the internal temperature about 5° C. (addition completeafter approximately 45 minutes). After one hour at 5° C., TLC indicatedmost of starting material was consumed. One mL of methanesulfonylchloride was added, and the reaction mixture stirred for an additional30 minutes at 5° C. TLC indicated complete consumption of startingmaterial. The mixture then was washed with 1N HCl (3×250 mL), dried(Na₂SO₄), and concentrated to yield 113 g of Intermediate 90 as a yellowliquid (71%).

¹H NMR (400 MHz, CDCl₃) δ: 7.48-7.45 (m, 2H), 7.39-7.34 (m, 3H), 5.09(s, 2H), 3.16 (s, 3H).

INTERMEDIATE 91 3-(4-Fluorophenyl)prop-2-ynyl Methylsulfonate

Prepared from Intermediate 89 via the mesylation method of Intermediate90.

¹H NMR (400 MHz, CDCl₃) δ: 7.47-7.44 (q, 2H), 7.04 (t, 2H), 5.07 (s,2H), 3.15 (s, 3H).

INTERMEDIATE 92 3-[4-(Trifluoromethyl)phenyl]prop-2-ynyl Methylsulfonate

Prepared from Intermediate 88 via the mesylation method of Intermediate90.

¹H NMR (400 MHz, CDCl₃) δ:7.62-7.56 (m, 4H), 5.09 (s, 2H), 3.16 (s, 3H).

EXAMPLE 3

Preparation of four stereoisomers from reduction of Intermediate 36.Sodium borohydride (2.0 mmol, 0.075 g) was added to Intermediate 36 (1.3mmol, 0.50 g) dissolved in 10 mL of ethanol. The complete reaction wasdried in vacuo after 1 hour. The resulting oil was extracted three timeswith EtOAc from, water, then the combined extracts were washed withbrine and dried over MgSO₄. The mixture of two racemates was obtained asan oil.

¹H NMR δ: 6.80 (d, 1H); 6.67 (d, 2H); 4.72 (bd, 1H); 3.86-3.95 (bm, 1H);3.83 (s, 3H); 3.64-3.78 bm, 1H); 3.74 (s, 3H); 3.33 (dd, 1H); 2.16 (d,3H); 1.79-1.92 (bm, 4H); 1.59-1.63 (bm, 2H); 1.01 (sd, 3H).

The mixture of racemates was dissolved in 50% acetonitrile and 50% waterat a concentration of 50 mg/mL and purified in portions on a C-18 column(250×10 mm) using a water/acetonitrile/0.5% TFA gradient. Appropriatefractions were collected, combined, and dried to oils.

¹H NMR for minor racemate δ: 6.75-6.82 (bm, 3H); 4.75 (bd, 1H); 3.83 (s,3H); 3.64-3.81 (bm, 1H); 3.74 (s, 3H); 3.54-3.61 (bm, 2H); 3.28 (dd,1H); 1.81-1.94 (bm, 5H); 1.58-1.65 (bm, 4H); 1.15 (dd, 3H); 0.75 (s,3H).

¹H NMR for the major racemate δ: 6.76-6.83 (bm, 3H); 4.74 (bd, 1H);3.77-3.89 (bm, 1H); 3.83 (s, 3H); 3.73 (s, 3H); 3.65 (quin, 1H);3.25-3.32 (bm, 3H); 1.77-1.96 (bm, 7H); 1.58-1.61 (bm, 2H); 1.13 (d,3H); 0.92 (s, 3H).

Chiral Separation of the Alcohols

Two columns were required to separate the four diastereomers by HPLC.The first dextrose-based column (8×30 cm) was used to separate the R,R,Sisomer from the others. Ten mL (7.1 mg/mL stock solution) of crudemixture in column buffer was introduced then eluted at 1 mL/min withisocratic hexanes (85%) and isopropanol (15%), collecting theappropriate fractions. The remaining diastereomers were purified on adifferent dextrose-based column (10×50 cm). Again, 10 mL (7.1 mg/mLstock solution) was injected, then eluted at 1 mL/min with isocratichexanes (95%) and isopropanol (5%). The appropriate fractions werecollected, combined and dried to oils.

EXAMPLE 4

R¹=2-indanyl; R³=CO₂CH₃

trans-(±)-3-(1-Hydroxyethyl)-4-[3-(indan-2-yloxy)-4-methoxyphenyl]-3-methylpyrrolidine-1-carboxylicAcid Methyl Ester (2 Carbinol Diastereomers)

A solution of Intermediate 35 (racemic) (300 mg, 0.71 mmol, 1 eq) inethanol (10 mL) was treated with sodium borohydride (54 mg, 1.42 mmol, 2eq). The mixture was stirred 10 min at room temperature, treated with 1N HCl (50 mL), and extracted with EtOAc (3×25 mL). The combined organicextracts were washed with 1 N HCl (25 mL), water, sat. NaHCO₃ (25 mL),water (25 mL), and brine (25 mL), dried over Na₂SO₄, and concentrated invacuo. A portion of the crude residue was purified by HPLC (Vydac 20×250mm C-18 “Protein and Peptide” column, 8 min. gradient of 50-75%acetonitrile in water with each solvent containing 0.05% TFA, flow rateof 20 mL/min) to yield the separated diastereomers in a 2:1 ratio ascolorless syrups (75 and 37 mg respectively, in order of elution fromcolumn).

Isomer 1: ¹H NMR (300 MHz, CDCl₃) δ: 7.24-7.15 (m, 4H), 6.83 (br s, 3H),5.21-5.12 (m, 1H), 3.91-3.59 (m, 3H), 3.81 (s, 3H), 3.73 (s, 3H),3.40-3.18 (m, 7H), 1.14 (d, J=6.3 Hz, 3H), 0.94 (s, 3H). Isomer 2: ¹HNMR (300 MHz, CDCl₃) δ: 7.23-7.15 (m, 4H), 6.85-6.82 (m, 3H), 5.22-5.10(m, 1H), 3.89-3.67 (m, 3H), 3,81 (s, 3H), 3,75 (s, 3H), 3,64-3.52 (m,2H), 3.40-3.15 (m, 5H), 1.20-1.13 (m, 3H), 0.78 (s, 3H).

The compounds of Examples 5 and 6 were prepared in the same manner asExample 4:

EXAMPLE 5

R¹=2-norbornyl; R³=CO₂CH₃

trans4-[3-Exo-(Bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl]-3-(1-hydroxyethyl)-3-methylpyrrolidine-1-carboxylicAcid Methyl Ester (2 Carbinol Diastereomers)

Intermediate 38 was reduced and separated as above to give two isomers:

Isomer 1: ¹H NMR (300 MHz, CDCl₃) δ: 6.82-6.72 (m, 3H), 4.15 (br s, 1H),3.88-3.59 (m, 3H), 3.87 (s, 3H), 3.73 (s, 3H), 3.32-3.24 (m, 3H),2.50-2.47 (m, 1H), 2.34-2.28 (m, 1H), 1.77-1.50 (m, 5H), 1.21-1.12 (m,6H), 0.92 (s, 3H). Isomer 2: ¹H NMR (300 MHz, CDCl₃) δ: 6.82-6.72 (m,3H), 4.19-4.15 (m, 1H), 3.85-3.54 (m, 5H), 3.83 (s, 3H), 3.74 (s, 3H),3.30/3.23 (2 d, J=10.4/10.4 Hz, 1H), 2.49-2.46 (m, 1H), 2.32 (br s, 1H),1.76-1.70 (m, 2H), 1.65-1.44 (m, 3H), 1.21-1.14 (m, 6H), 0.75 (s, 3H).

EXAMPLE 6

R¹=PhCH₂CH₂CH(CH₃); R³=CO₂CH₃

trans-3-(1-Hydroxyethyl)-4-[4-methoxy-3-(1-methyl-3-phenylpropoxy)phenyl]-3-methylpyrrolidine-1-carboxylicAcid Methyl Ester (2 Carbinol Diastereomers)

Intermediate 39 was reduced and separated as above to give two isomers:

Isomer 1: ¹H NMR (300 MHz, CDCl₃) δ: 7.30-7.25 (m, 3H), 7.22-7.15 (m,3H), 6.85-6.69 (m, 3H), 4.34-4.27 (m, 1H), 3.87-3.54 (m, 3H), 3.84 (s,3H), 3.73/3.72 (2 s, 3H), 3.31-3.20 (m, 3H), 2.83-2.75 (m, 2H),2.18/2.08 (m, 1H), 1.95-1.84 (m, 1H), 1.34/1.31 (2 s, 3H), 1.12 (d,J=6.3 Hz, 3H), 0.89 (br s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ: 156.0, 150.3,147.8, 142.2, 131.3/131.1, 128.9, 128.8, 125.2, 121.7, 117.1, 112.5,77.6, 75.3/75.1, 74.1/74.0, 56.3, 56.2/55.8, 52.9, 52.0/51.5/51,2,49.9/49.1, 38.5/38.4, 32.2, 20.3, 19.0/18.9, 14.6/14.5. Isomer 2: ¹H NMR(300 MHz, CDCl₃) δ: 7.29-7.24 (m, 2H) 7.20-7.14 (m, 3H), 6.84-6.69 (m,3H), 4.35-4.24 (m, 1H), 3.85/3.84 (2 s, 3H), 3.83-3.45 (m, 5H) 3.75 (s,3H), 3.31-3.23 (m, 1H), 2.88-2.76 (m, 2H) 2,21-2.07 (m, 1H), 1.95-1.83(m, 1H), 1.34/1.32 (2 s, 3H), 1.15-1.11 (m, 3H), 0.73 (br s, 3H). ¹³CNMR (75 MHz, CDCl₃) δ: 156.1, 149.9, 147.4, 142.3, 129.5/129.4, 128.9,128.7, 126.2, 122.1/-121.8, 117.9/117.7/117.4, 112.0, 77.6,75.3/75.0/-74.9, 69.4/69.3, 56.3, 53.2, 53.1, 49.5/49.3/49.1/-48.6,46.5/46.0, 38.5/38.4/38.3, 32.1, 20.3, 20.0, 17.7.

The following compounds were prepared from chiral free pyrrolidineIntermediate 68.

EXAMPLE 7

R¹=C₅H₉; R³=COCH₂OCH₂Ph

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(phenylmethoxy)ethan-1-one

N-Acylation Procedure

To a stirred solution Intermediate 68 (42.6 mg, 0.13 mmol) in1,4-dioxane (0.4 mL) was added, successively, aqueous K₂CO₃ (0.8 mL of0.65 M, 4 eq.) and a solution of the acid chloride (R₃—Cl) (21 μL, 0.13mmol) in 1,4-dioxane (0.4 mL) at room temperature. The resultingsolution was allowed to stir at room temperature for 4 hours. Thereaction was diluted with EtOAc (30 mL), then washed successively withwater (20 mL) and brine (20 mL), dried (MgSO₄), filtered, andconcentrated in vacuo to provide Example 7 as a slightly tan foam (46.5mg, 99%).

¹H NMR (400 MHz, CDCl₃) δ: mixture of rotomers): 7.40-7.31 (m, 5H),6.80-6.72 (m, 3H), 4.73 (c, 1H), 4.67 (s, 2H), 4.14 (s, 2H), 3.82 (s,3H), 3.79-3.45 (m, 5H), 3.22 (d, 1H), 1.92-1.80 (c, 6H), 1.61-1.55 (c,2H), 1.14 (dd, 3H), 0.73 (d, 3H). LRMS (Electrospray, positive): Da/e468.4 (m+1).

EXAMPLE 8

R¹=C₅H₉; R³=COCH₂OH

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyethan-1-one

Example 7 (35 mg, 75 μmol) was subjected to the debenzylation procedureof Intermediate 31 to give Example 8 (24 mg, 84%).

¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 6.91-6.82 (m, 3H), 4.83(c, 1H), 4.22 (c, 1H), 3.87-3.22 (m, 11H), 1.93-1.73 (m, 6H), 1.69-1.59(m, 2H), 1.11 (dd, 3H), 0.75 (br s, 3H). LRMS (Electrospray, positive):Da/e 378.4 (m+1).

EXAMPLE 9

R¹=C₅H₉; R³=COCH₂CH₂N (H) CO₂CH₂Ph

N-{3-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-3-oxopropyl}(phenylmethoxy)carboxamide

Prepared from Intermediate 68 via the acylation procedure of Example 7.The p-nitrophenylester of N-Cbz-beta-alanine was used in place of theacid chloride.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.38-7.28 (m, 5H),6.92-6.83 (m, 3H), 5.06 (c, 2H), 4.86 (s, 2H), 4.84 (c, 1H), 3.81-3.27(m, 10H), 2.59 (c, 2H), 1.98-1.69 (c, 6H), 1.64-1.57 (c, 2H), 1.09 (d,3H), 0.73 (d, 3H). LRMS (Electrospray, positive): Da/e 525.3 (m+1).

EXAMPLE 10

R¹=C₅H₉; R³=COCH₂CH₂NH₂

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-3-aminopropan-1-one

Prepared from Example 9 via the debenzylation procedure of Intermediate31.

¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 6.91-6.79 (m, 3H), 4.81(c, 1H), 3.92-3.29 (m, 11H), 3.01 (br s, 2H), 2.61-2.58 (m, 2H),1.95-1.73 (m, 6H), 1.68-1.58 (m, 2H), 1.10 (dd, 3H), 0.76 (d, 3H). LRMS(Electrospray, positive): Da/e 391.4 (m+1).

EXAMPLE 11

R¹=C₅H₉; R³=COCH₂CH₂CO₂CH₂Ph

Phenylmethyl4-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-4-oxobutanoate

Prepared from Intermediate 68 via the acylation procedure of Example 7.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.41-7.31 (m, 5H),6.84-6.75 (m, 3H), 5.14 (d, 2H), 4.74 (c, 1H), 3.94-3.44 (m, 8H), 3.27(d, 1H), 2.80-2.73 (m, 2H), 2.67-2.58 (m, 2H), 1.96-1.81 (m, 6H),1.68-1.56 (m, 2H), 1.15 (dd, 3H), 0.75 (d, 3H). LRMS (Electrospray,positive): Da/e 510.3 (m+1).

EXAMPLE 12

R¹=C₅H₉; R³=COCH₂CH₂CO₂H

4-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-4-oxobutanoicAcid

Prepared from Example 11 via the debenzylation procedure of Intermediate31.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.80-6.72 (m, 3H), 4.74(c, 1H), 3.98-3.54 (m, 10H), 3.40 (d, 1H), 3.24 (d, 1H), 2.69 (c, 2H),1.95-1.74 (m, 6H), 1.69-1.51 (m, 2H), 1.14 (dd, 3H), 0.74 (d, 3H). LRMS(Electrospray, positive): Da/e 420.3 (m+1).

EXAMPLE 13

R¹=C₅H₉; R³=COCH₂N(H)CO₂CH₂Ph

N-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoethyl}(phenylmethoxy)carboxamide

Prepared from Intermediate 68 via the acylation procedure of Example 7.The p-nitrophenylester of N-Cbz-glycine was used in place of the acidchloride.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.40-7.25 (m, 5H),6.92-6.81 (m, 3H), 5.11 (s, 2H), 4.87 (s, 2H), 4.82 (c, 1H) 4.11-3.28(m, 9H), 1.95-1.70 (m, 6H), 1.65-1.55 (m, 2H), 1.10 (br s, 3H), 0.76 (brs, 3H). LRMS (Electrospray, positive): Da/e 511.6 (m+1).

EXAMPLE 14

R¹=C₅H₉; R³=COCH₂NH₂

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-aminoethan-1-one

Prepared from Example 13 via the debenzylation procedure of Intermediate31.

¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 6.91-6.82 (m, 3H), 4.80(c, 1H), 3.91-3.28 (m, 11H), 1.90-1.75 (m, 6H), 1.66-1.57 (m, 2H), 1.09(dd, 3H), 0.74 (d, 3H). LRMS (Electrospray, positive): Da/e 377.2 (m+1).

EXAMPLE 15

R¹=C₅H₉; R³=CO-4-Methyl-piperazine

3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl-4-methylpiperazinylKetone

Intermediate 68 (30.2 mg, 94 mmol) was dissolved in 1,2-dichloroethane(400 μL) and cooled to 0° C., then carbonyl diimidazole (16 mg, 94 μmol)was added. The reaction was stirred at 0° C. for 1.5 hours, followed bythe addition of 1-methylpiperazine (21 μL, 180 μmol). The solution washeated to 80° C. for 60 hours. After cooling, the reaction mixture wasdiluted with CH₂Cl₂ and washed three times with 6% NaHCO₃, dried overNa₂SO₄ and concentrated in vacuo. The residue was chromatographed onSiO₂ with EtOAc (15.5 mg).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.83-6.78 (m, 3H), 4.76(c, 1H), 4.06-3.77 (m, 18H), 3.61 (q, 1H), 3.39 (br s, 1H), 1.93-1.78(m, 6H), 1.63-1.57 (m, 2H), 1.15 (br s, 3H), 0.81 (br s, 3H). LRMS(Electrospray, positive): Da/e 446.4 (m+1).

EXAMPLE 16

R¹=C₅H₉; R³=CO-N-morpholine

3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinylmorpholin-4-yl Ketone

Prepared from Intermediate 68 using morpholine and carbonyldiimidazoleas a coupling reagent by the procedure set forth in Example 15.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.84-6.77 (m, 3H), 4.76(c, 1H), 3.88-3.52 (m, 12H), 3.41 (dd, 1H), 3.38 (dd, 1H), 3.28 (dd,1H), 3.25 (dd, 1H), 3.10 (d, 1H), 1.95-1.81 (m, 6H), 1.62-1.54 (m, 2H),1.15 (d, 3H), 0.75 (s, 3H). LRMS (Electrospray, positive): Da/e 433.3(m+1).

EXAMPLE 17

R¹=C₅H₉; R³=COCH₂O-Menthol; (1S)-Carbinol Isomer

1-[3-((1S)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-[(2S,1R,5R)-5-methyl-2-(methylethyl)cyclohexyloxy]-ethan-1-one

Prepared from the S-carbinol isomer Intermediate 69 by the Hunig's basemediated acylation procedure of Intermediate 69.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.82-6.75 (m, 3H), 4.74(c, 1H), 4.19 (dd, 1H), 4.04 (dd, 1H), 3.92-3.76 (m, 5H), 3.47-3.19 (m,5H), 2.26 (c, 1H), 2.13 (c, 1H), 1.94-1.80 (m, 6H), 1.65-1.53 (m, 4H),1.51-1.19 (m, 4H), 1.14 (d, 3H), 0.95-0.84 (m, 9H), 0.79 (d, 3H). LRMS(Electrospray, positive): Da/e 516.3 (m+1).

EXAMPLE 18

R¹=C₅H₉; R³=CO-4-(2-Methylthiazole)

3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl2-methyl-(1,3-thiazol-4-yl)ketone

Prepared from Intermediate 68 via the EDCI coupling procedure of Example27 from 2-methyl-1,3-thiazole-4-carboxylic acid.

¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 7.98 (dd, 1H), 6.92-6.82(m, 3H), 4.84 (c, 1H), 4.27 (t, 0.5H), 4.16 (t, 0.5H), 4.08 (t, 0.5H),3.96 (d, 0.5H), 3.85-3.47 (m, 7H), 2.72 (dd, 3H), 1.88-1.72 (m, 6H),1.68-1.56 (m, 2H), 1.14 (dd, 1.5H), 1.08 (dd, 1.5H), 0.82 (d, 1.5H),0.73 (d, 1.5H). LRMS (Electrospray, positive): Da/e 445.4 (m+1).

EXAMPLE 19

R¹=C₅H₉; R³=SO₂-3-pyridyl

3-{[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]sulfonyl}-pyridine

To a stirred solution of Intermediate 68 (32 mg, 0.1 mmol) in dioxane(0.3 mL) were added, successively, aqueous K₂CO₃ (0.6 mL of 0.65 M, 4eq.) and a solution of the R³-sulfonyl chloride (26 mg, 0.12 mmol) indioxane (0.3 mL) at room temperature. The resulting solution was allowedto stir at room temperature for 2 hours. The reaction was diluted with1:1 hexanes:EtOAc (30 mL) and washed successively with water (20 mL) andbrine (20 mL), then dried (MgSO₄), filtered, and concentrated in vacuoto provide Example 19 as a slightly orange foam (36 mg, 78%).

¹H NMR (400 MHz, CDCl₃) δ: 9.11 (d, 1H, J=2.2 Hz), 8.83 (dd, 1H, J=1.6,4.8 Hz), 8.17 (ddd, 1H, J=1.5, 2.4, 8.1 Hz), 7.50 (ddd, 1H, J=0.8, 4.9,8.0 Hz), 6.74 (d, 1H, J=8.5 Hz), 6.68 (d, 1H, J=2.1 Hz), 6.62 (dd, 1H,J=2.1, 8.3 Hz), 4.70 (c, 1H), 3.80 (s, 3H), 3.66-3.62 (m, 2H), 3.51-3.43(m, 3H), 3.24 (d, 1H, J=13.3 Hz), 1.91-1.62 (m, 6H), 1.60-1.55 (m, 2H),1.08 (d, 3H, J=6.4 Hz), 0.62 (s, 3H). LRMS (Electrospray, positive):Da/e 461.2 (m+1).

EXAMPLE 20

R¹=2-indanyl; R³=COCH₂OCH₂Ph

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yl-oxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(phenylmethoxy)ethan-1-one

Prepared from Intermediate 51 (50 mg, 0.14 mmol) by the Hunig's baseacylation procedure of Intermediate 74 using benzyloxyacetyl chloride(22.5 μL, 0.14 mmol) to provide Example 20 as a clear oil (48 mg, 68%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.41-7.16 (m, 9H),6.84-6.79 (m, 3H), 5.17 (c, 1H), 4.66 (d, 2H), 4.19-4.11 (m, 2H), 3.96(dd, 0.5H), 3.83-3.54 (m, 7H), 3.47 (d, 0.5H), 3.38-3.29 (m, 2H),3.24-3.17 (m, 3H), 1.57 (br t, 1H), 1.15 (dd, 3H), 0.75 (s, 3H). LRMS(Electrospray, positive): Da/e 516.8 (m+1).

EXAMPLE 21

R¹=2-indanyl; R³=COCH₂OH

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yl-oxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyethan-1-one

Prepared from Example 20 via the debenzylation procedure of Intermediate31.

¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 7.24-7.18 (m, 2H),7.14-7.12 (m, 2H), 6.92-6.86 (m, 3H), 5.20 (c, 1H), 4.27-4.14 (m, 2H),3.90-3.50 (m, 6H), 3.41 (d, 1H), 3.34-3.24 (m, 4H), 3.13-3.08 (m, 2H),1.12 (dd, 3H), 0.77 (br s, 3H).

LRMS (Electrospray, positive): Da/e 426.5 (m+1).

EXAMPLE 22

R¹=2-indanyl; R³=COCO₂CH₃

Methyl2-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoacetate

Prepared from Intermediate 51 and methyl oxalyl chloride via the Hunig'sbase coupling procedure of Intermediate 74.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.82-6.75 (m, 3H), 4.74(c, 1H), 4.01 (d, 1H), 3.98-3.56 (m, 10H), 3.50 (dd, 1H), 1.93-1.84 (m,6H), 1.64-1.56 (m, 2H), 1.45 (dd, 1H), 1.16 (dd, 3H), 0.79 (s, 1.5H),0.75 (s, 1.5H). LRMS (Electrospray, positive): Da/e 406.2 (m+1).

EXAMPLE 23

R¹=2-Indanyl; R³=COC(CH₃)2N(H)CO₂CH₂Ph

N-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1,1-dimethyl-2-oxoethyl}(phenylmethoxy)carboxamide

PyBrOP Coupling Procedure

To a stirred solution of bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBrOP, 70 mg, 0.15 mmol),N-carbobenzyloxy-2-methylalanine (35.5 mg, 0.15 mmol), and Hunig's base(78 μL, 0.45 mmol) in dry dimethylformamide (1 mL) was addedIntermediate 51 (50 mg, 0.14 mmol) at room temperature under a nitrogenatmosphere. The resulting golution wag allowed to stir at roomtemperature for 16 hours, then heated to 70° C. for 5 hours. Thereaction was allowed to cool to room temperature, then concentrated invacuo. The residue was purified via radial chromatography (1 mm platewith 3% MeOH in CH₂Cl₂) to provide Example 23 as a white foam (20 mg,24%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.43-7.15 (m, 9H),6.82-6.62 (m, 3H), 5.64 (br s, 0.5H), 5.51 (br s, 0.5H), 5.15-5.08 (m,3H), 3.97-3.15 (m, 13H), 1.58 (br s, 6H), 1.13 (br d, 3H), 0.68 (br s,3H). LRMS (Electrospray, positive): Da/e 604.9 (m+18).

EXAMPLE 24

R¹=2-Indanyl; R³=COC(CH₃) ₂NH₂

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yl-oxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-amino-2-methylpropan-1-one

Prepared from Example 23 via the debenzylation procedure of Intermediate31.

¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 7.21-7.16 (m, 2H),7.15-7.12 (m, 2H), 6.94-6.87 (m, 3H), 5.22 (c, 1H), 4.05 (d, 1H), 3.88(c, 1H), 3.77-3.69 (m, 4H), 3.60-3.52 (c, 2H), 3.40-3.29 (c, 2H), 3.22(q, 1H), 3.13-3.09 (c, 2H), 1.37 (d, 6H), 1.13 (br s, 3H), 0.80 (s, 3H)LRMS (Electrospray, positive): Da/e 453.5 (m+1).

EXAMPLE 25

R¹=2-Indanyl; R³=CO₂CH₃

Methyl3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylate

Prepared from Intermediate 51 via the Hunig's base mediated acylationprocedure of Intermediate 74 using methyl chloroformate.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.24-7.16 (m, 4H),6.86-6.82 (m, 3H), 5.18 (c, 1H), 3.85-3.56 (m, 8H), 3.38-3.30 (m, 3H),3.25-3.19 (m, 3H), 1.51 (d, 0.5H), 1.47 (d, 0.5H), 1.16 (t, 3H), 0.77(s, 3H). LRMS (Electrospray, positive) Da/e 426.5 (m+1), 443.3 (m+18).

EXAMPLE 26

R¹=2-Indanyl; R³=COCH₂C(CH₃)₂CO₂H

4-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2,2-dimethyl-4-oxobutanoicAcid

A thick walled glass tube fitted with a threaded cap was charged withIntermediate 51 (20 mg, 0.05 mmol) and 2,2-dimethylsuccinic anhydride(25.8 mg, 0.05 mmol). The tube was sealed, then heated at 150° C. for 30minutes. The reaction mixture was allowed to cool to room temperature toprovide Example 26 (containing about 15-20% of the other regioisomer) asa brown solid (22 mg, 82%).

¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 7.22-7.20 (m, 2H),7.15-7.12 (m, 2H), 6.96-6.85 (m, 3H), 5.23 (c, 1H), 3.92-3.49 (m, 7H),3.37-3.28 (m, 4H), 3.13-3.09 (m, 2H), 2.73-2.55 (m, 2H), 1.30 (br s,6H), 1.12 (t, 3H), 0.76 (d, 3H). LRMS (Electrospray, negative): Da/e494.5 (m−1).

EXAMPLE 27

R¹=2-Indanyl; R³=CO-4-(2-Methylthiazole)

3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl2-methyl(1,3-thiazol-4-yl)ketone

EDCI Coupling Procedure

To a stirred solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (42.3 mg, 0.214 mmol) in dry CH₂Cl₂ (1 mL) was added2-methyl-1,3-thiazole-4-carboxylic acid (30.7 mg, 0.214 mmol) at roomtemperature under a nitrogen atmosphere. The resulting bright redmixture was allowed to stir for 1 hour, then Intermediate 51 (75 mg,0.204 mmol) was added in one portion. After stirring at room temperatureovernight, the reaction was concentrated at reduced pressure and theresidue purified via radial chromatography (1 mm plate with 3% MeOH inCH₂Cl₂) to provide Example 27 as a clear film (21 mg, 20%).

¹H NMR (400 MHz, CDCl₃; mixture of rotomers) δ: 7.91 (s, 0. 5H), 7.88(s, 0. 5H), 7.25-7.20 (m, 2H), 7.18-7.16 (m, 2H), 6.90-6.82 (m, 3H),5.19 (c, 1H), 4.33 (dd, 0. 5H), 4.23 (t, 0.5H), 4.15 (d, 0.5H), 4.10(dd, 0.5H), 3.99 (t, 0.5H), 3.85 (d, 0.5H), 3.81 (s, 3H), 3.77-3.58 (m,3H), 3.38-3.31 (m, 2H), 3.24-3.20 (m, 2H), 2.74 (s, 1.5H), 2.71 (s,1.5H), 1.93 (s, 0.5H), 1.61 (d, 0.5H), 1.22 (d, 1.5H), 1.18 (d, 1.5H),0.86 (s, 1.5H), 0.75 (s, 1.5H). LRMS (Electrospray, positive): Da/e493.6 (m+1).

EXAMPLE 28

R¹=2-Indanyl; R³=CO-3-tetrahydrofuranyl

3-((1R)-1-Hydroxyethyl)(4S,3R)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylcyclopentyloxolan-3-yl ketone (Mixture of 2 Diastereomers at the TetrahydrofuranylPoint of Attachment)

Prepared from Intermediate 51 via the Hunig's base coupling procedure ofIntermediate 74 using tetrahydrofuran-3-carbonyl chloride.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.40-7.20 (m, 2H),7.19-7.16 (m, 2H), 6.86-6.83 (m, 3H), 5.18 (c, 1H), 4.15-4.04 (m, 1H),3.98-3.15 (m, 13H), 2.31-2.09 (m, 2H), 1.75 (br s, 1H), 1.26 (t, 1.5H),1.17 (t, 1.5H), 0.80 (d, 1.5H), 0.78 (s, 1.5H). LRMS (Electrospray,positive): Da/e 466.3 (m+1).

EXAMPLE 29

R¹=2-Indanyl; R³=COCH₂N(H)CO₂CH₂Ph

N-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoethyl}(phenylmethoxy)carboxamide

Prepared from Intermediate 51 via the PyBrOP coupling procedure ofExample 23 using N-benzyloxycarbonyl glycine.

¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 7.35-7.20 (m, 9H),6.91-6.88 (m, 3H), 5.22 (br s, 1H), 5.10 (s, 2H), 4.07-3.09 (m, 15H),1.13 (t, 3H), 0.78 (s, 3H).

EXAMPLE 30

R¹=2-Indanyl; R³=COCH₂NH₂

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-aminoethan-1-one

Prepared from Example 29 via the debenzylation procedure of Intermediate31.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.22-7.19 (m, 2H),7.18-7.15 (m, 2H), 6.84 (d, 1H), 6.81 (d, 2H), 5.17 (c, 1H), 3.96 (dd,0.5H), 3.81-3.43 (m, 9H), 3.37-3.30 (m, 1.5H), 3.23-3.13 (m, 2H), 2.99(br s, 2H), 1.15 (t, 3H), 0.75 (d, 3H). LRMS (Electrospray, positive):Da/e 425.5(m+1).

EXAMPLE 31

R¹=2-Indanyl; R³=2-Pyridyl

(1R)-1-[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-(2-pyridyl)pyrrolidin-3-yl]ethan-1-ol

Aryl Bromide Coupling Procedure

To a stirred mixture of Intermediate 51 (115 mg, 0.31 mmol) and K₂CO₃(173 mg, 1.2 mmol) in dry DMF (2 mL) was added 2-bromopyridine (0.12 mL,1.2 mmol) via syringe at room temperature under a nitrogen atmosphere.The resulting mixture was heated at 90° C. for 22 hours, then allowed tocool to room temperature. The reaction was diluted with water (60 mL),and extracted with EtOAc (3×30 mL). The combined organic extracts werewashed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.

The residue was purified via flash chromatography on silica gel (100%EtOAc) to provide Example 31 (73.4 mg, 53%).

¹H NMR (400 MHz, CDCl₃) δ: 8.18 (ddd, 1H), 7.45 (ddd, 1H), 7.26-7.21 (m,2H), 7.19-7.16 (m, 2H), 6.92-6.88 (m, 2H), 6.83 (d, 1H), 6.54 (ddd, 1H),6.40 (d, 1H), 5.17 (c, 1H), 3.86-3.78 (m, 5H), 3.70 (d, 1H), 3.67 (d,1H), 3.38-3.30 (m, 3H). LRMS (Electrospray, positive): Da/e 445.4 (m+1).

EXAMPLE 32

R¹=2-Indanyl; R³=3-Pyridyl

(1R)-1-[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-(3-pyridyl)pyrrolidin-3-yl]ethan-1-ol

Palladium-catalyzed Coupling Procedure

To a stirred solution of Intermediate 51 (79.3 mg, 0.22 mmol) and sodiumt-butoxide (29 mg, 0.31 mmol) in dry toluene (3 mL) was added,sequentially, 3-bromopyridine (22.9 mL, 0.24 mmol),tris(dibenzylideneacetone)dipalladium(0) (3.9 mg, cat.), and(R)(+)-1,1′-bi-2-naphthol (5.4 mg, cat.) at room temperature under anitrogen atmosphere. The resulting mixture was heated at 80° C. for 3hours, then allowed to cool to room temperature. The reaction then wasdiluted with EtOAc (40 mL), washed with brine, dried (Na₂SO₄), filtered,and concentrated in vacuo. The residue was purified via flashchromatography on silica gel (40% EtOAc in hexanes) to provide Example32 (72.1 mg, 75%).

¹NMR (400 MHz, CDCl₃) δ: 7.98 (d, 1H), 7.91 (d, 1H), 7.24-7.15 (m, 4H),7.11 (dd, 1H), 6.90-6.82 (m, 4H), 5.15 (c, 1H), 3.81-3.72 (m, 4H),3.70-3.62 (m, 4H), 3.35-3.11 (m, 5H), 1.24 (d, 3H), 0.84 (s, 3H). LRMS(Electrospray, positive): Da/e 445.3 (m+1).

EXAMPLE 33

R¹=2-Indanyl; R³=2-Pyrimidyl

(1R)-1-[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-pyrimidin-2-ylpyrrolidin-3-yl]ethan-1-ol

Prepared from Intermediate 51 via the aryl bromide coupling procedure ofExample 31.

¹H NMR (400 MHz, CDCl₃) δ: 8.34 (dd, 2H), 7.24-7.18 (m, 2H), 7.16 (dd,2H), 6.94-6.84 (m, 2H), 6.82 (c, 1H), 6.48 (t, 1H), 5.16 (c, 1H),4.12-3.75 (m, 7H), 3.64 (br d, 1H), 3.52 (d, 1H), 3.36 (d, 1H), 3.32 (d,1H), 3.24 (t, 1H), 3.20 (t, 1H), 1.23 (d, 3H), 0.83 (s, 3H). LRMS(Electrospray, positive): Da/e 446.4 (m+1).

EXAMPLE 34

R¹=C₅H₉; R³=2-Pyridyl

(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-(2-pyridyl)pyrrolidin-3-yl]ethan-1-ol

Prepared from Intermediate 68 via the aryl bromide coupling procedure ofExample 31.

¹H NMR (400 MHz, CDCl₃) δ: 8.18 (ddd, 1H), 7.46 (ddd, 1H), 6.89-6.82 (m,3H), 6.54 (ddd, 1H), 6.40 (d, 1H), 4.75 (c, 1H), 3.92-3.65 (m, 8H), 3.36(d, 1H), 1.94-1.80 (m, 6H), 1.66-1.55 (m, 2H). LRMS (Electrospray,positive): Da/e 397.4 (m+1).

EXAMPLE 35

R¹=C₅H₉; R³=3-Pyridyl

(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-(3-pyridyl)pyrrolidin-3-yl]ethan-1-ol

Prepared from Intermediate 68 via the palladium catalyzed couplingprocedure of Example 32.

¹H NMR (400 MHz, CDCl₃) δ: 8.00 (d, 1H), 7.93 (d, 1H), 7.12 (dd, 1H),6.86-6.78 (m, 4H), 4.73 (c, 1H), 3.95-3.59 (m, 8H), 3.12 (d, 1H),1.90-1.79 (m, 6H), 1.60-1.54 (m, 2H), 1.22 (d, 3H), 0.82 (s, 3H). LRMS(Electrospray, positive): Da/e 397.2 (m+1).

EXAMPLE 36

R¹=(4-Pho)—Ph; R³=CO₂CH₃

Methyl3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenoxyphenoxy)phenyl]-3-methylpyrrolidinecarboxylate

Cryptand Etherification Procedure

To a stirred suspension of sodium hydride (16 mg of a 60% dispersion inmineral oil, 0.40 mmol) in dry anisole (2 mL) was added Intermediate 74(100 mg, 0.32 mmol), portionwise, over 5 minutes with H₂ evolution, atroom temperature under a nitrogen atmosphere. After stirring for 30minutes, tris[2-(2-methoxyethoxy)ethyl]amine (10 mL, 0.03 mmol), copper(I) chloride (10 mg, 0.10 mmol), and 4-bromobiphenyl ether were added,and the resulting mixture heated at reflux for 20 hours. The anisolethen was removed via vacuum distillation. The residue dissolved in EtOAc(25 mL), and filtered through GF/F filter paper. The filtrate was washedwith 1N aq. HCl (20 mL), dried (Na₂SO₄), filtered, and concentrated invacuo. The residue was purified via radial chromatography (2 mm silicaplate with 1:1 hexanes:EtOAc) to provide Example 36 as a tan oil (40 mg,26%).

¹H NMR (400 MHz, CDCl₃; mixture of rotomers) δ: 7.30 (dd, 2H), 7.09-6.86(m, 10H), 3.88-3.49 (m, 11H), 3.28 (d, 0.5H), 3.19 (d, 0.5H), 1.93 (brs, 0.5H), 1.83 (br s, 0.5H), 1.12 (dd, 3H), 0.71 (br s, 3H) LRMS(Electrospray, positive): Da/e 478.2 (m+1).

EXAMPLE 37

R¹=(4-PhO)—Ph; R³=CO₂CH₃: Other Carbinol Diastereomer

Methyl3-((1S)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenoxyphenoxy)phenyl]-3-methylpyrrolidinecarboxylate

Prepared from the (1S)-carbinol isomer Intermediate 75 via the cryptandetherification procedure of Example 36.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.32 (t, 2H), 7.07 (dt,1H), 7.03-6.74 (m, 9H), 3.91-3.55 (m, 9H), 3.35-3.17 (m, 3H), 2.16 (d,0.5H), 1.38 (br s, 0.5H), 1.12 (d, 3H), 0.85 (s, 3H). LRMS(Electrospray, positive): Da/e 478.2 (m+1).

EXAMPLE 38

R¹=(4-Ph)—Ph; R³=CO₂CH₃

Methyl3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenylphenoxy)phenyl]-3-methylpyrrolidinecarboxylate

Prepared from Intermediate 74 via the cryptand etherification procedureof Example 36.

¹H NMR (400 MHz, CDCl3; mixture of rotomers) δ: 7.55 (d, 2H), 7.51 (d,2H), 7.42 (t, 2H), 7.31 (t, 1H), 7.05 (dt, 1H), 6.98-6.92 (m, 4H),3.87-3.54 (m, 11H), 3.29 (d, 0.5H), 3.19 (d, 0.5H), 1.64 (br s, 0.5H),1.57 (br s, 0.5H), 1.14 (dd, 3H), 0.74 (s, 3H). LRMS (Electrospray,positive): Da/e 462.2 (m+1).

EXAMPLE 39

R¹=(4-Ph)—Ph; R³=CO₂CH₃: Other Carbinol Diastereomer

Methyl3-((1S)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenylphenoxy)phenyl]-3-methylpyrrolidinecarboxylate

Prepared from the (1S)-carbinol isomer Intermediate 75 via the cryptandetherification procedure of Example 36.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.56 (d, 2H), 7.52 (dt,2H), 7.42 (t, 2H), 7.32 (t, 1H), 7.10-6.94 (m, 5H), 3.93-3.58 (m, 9H),3.38-3.18 (m, 3H), 1.13 (d, 3H), 0.88 (s, 3H). LRMS (Electrospray,positive): Da/e 462.2 (m+1).

EXAMPLE 40

R¹=Ph; R³=CO₂CH₃

Methyl3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(4-methoxy-3-phenoxyphenyl)-3-methylpyrrolidinecarboxylate

Prepared from Intermediate 74 via the cryptand etherification procedureof Example 36.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.32-7.26 (m, 3H), 7.02(t, 2H), 6.94-6.88 (m, 3H), 3.85-3.49 (m, 11H), 3.27 (d, 0.5H), 3.18 (d,0.5H), 1.12 (t, 3H) 0.71 (s, 3H) LRMS (Electrospray, positive): Da/e386.3 (m+1).

EXAMPLE 41

R¹=Ph; R³=CO₂CH₃: Other Carbinol Diastereomer

Methyl3-((1S)-1-Hydroxyethyl)(3S,4S)-4-(4-methoxy-3-phenoxyphenyl)-3-methylpyrrolidinecarboxylate

Prepared from the (1S)-carbinol isomer Intermediate 75 via the cryptandetherification procedure of Example 36.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.29 (t, 2H), 7.08-6.85(m, 6H), 3.87-3.52 (m, 9H), 3.34-3.16 (m, 3H), 1.11 (d, 3H), 0.85 (s,3H). LRMS (Electrospray, positive); Da/e 386.3 (m+1).

EXAMPLE 42

R¹=4-Fluorophenyl; R³=CO₂CH₃

Methyl3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(4-fluorophenoxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylate

Prepared from Intermediate 74 via the cryptand etherification procedureof Example 36.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.05-6.84 (m, 7H),3.89-3.45 (m, 11H), 3.28 (d, 0.5H), 3.18 (d, 0.5H), 1.13 (t, 3H), 0.71(br s, 3H). LRMS (Electrospray, positive): Da/e 404.4 (m+1).

EXAMPLE 43

R¹=CH₂C₃H₅; R³=CO₂CH₃

Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl)-3-methylpyrrolidinecarboxylate

K₂CO₃ Etherification Procedure

To a stirred mixture of Intermediate 74 (50 mg, 0.16 mmol) and powderedK₂CO₃ (24.6 mg, 0.18 mmol) in dry DMF (1 mL) was addedbromomethylcyclopropane (16.5 μL, 0.17 mmol) via syringe at roomtemperature under a nitrogen atmosphere. The resulting mixture washeated at 65° C. for 24 hours, then allowed to cool to room temperature.The reaction then was diluted with water (5 mL) and extracted with Et₂O(3×20 mL). The combined organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified via radialchromatography (1 mm silica plate with 30% EtOAc in hexanes) to provideExample 43 as a clear oil (30 mg, 51%).

¹H NMR (400 MHz, CDCl3; mixture of rotomers) δ: 6.84-6.75 (m, 3H),3.94-3.54 (m, 13H), 3.29 (d, 0.5H), 3.21 (d, 0.5H), 1.72 (br s, 0.5H),1.65 (br s, 0.5H), 1.30 (c, 1H), 1.13 (t, 3H), 0.73 (s, 3H), 0.61 (c,2H), 0.34 (c, 2H). LRMS (Electrospray, positive): Da/e 364.3 (m+1).

EXAMPLE 44

R¹=CH₂C₃H₅; R³=CO₂CH₃ Diastereomer

Methyl3-((1S)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylate

Prepared from (1S)-carbinol isomer Intermediate 75 via the K₂CO₃etherification procedure of Example 43 using bromomethylcyclopropane.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.84-6.75 (m, 3H),3.89-3.58 (m, 11H), 3.33-3.20 (m, 3H), 1.52 (br s, 1H), 1.31 (c, 1H),1.11 (d, 3H) 0.89 (s, 3H), 0.62 (m, 2H), 0.33 (m, 2H). LRMS(Electrospray, positive): Da/e 364.3 (m+1).

EXAMPLE 45

R¹=2-Thiazole; R³=CO₂CH₃

Methyl3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(4-methoxy-3-(1,3-thiazol-2-yloxy)phenyl)-3-methylpyrrolidinecarboxylate

Prepared from Intermediate 74 via the K₂CO₃ etherification procedure ofExample 43 using 2-bromothiazole.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.24-7.12 (m, 3H), 6.96(d, 1H), 6.75 (d, 1H), 3.89-3.52 (m, 11H), 3.29 (d, 0.5H), 3.20 (d,0.5H), 1.74 (br s, 1H), 1.14 (t, 3H), 0.74 (s, 3H). LRMS (Electrospray,positive): Da/e 393.2 (m+1).

EXAMPLE 46

R¹=2-Thiazole; R³=CO₂CH₃, Diastereomer

Methyl3-((1S)-1-Hydroxyethyl)(3S,4S)-4-(4-methoxy-3-(1,3-thiazol-2-yloxy)phenyl)-3-methylpyrrolidinecarboxylate

Prepared from (1S)-carbino) isomers Intermediate 75 via the K₂CO₃etherification procedure of Example 43.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.17 (d, 1H), 7.16 (d,1H), 7.11 (dd, 1H), 6.97 (d, 1H), 6.75 (d, 1H), 3.86-3.59 (m, 9H),3.42-3.19 (m, 3H), 1.52 (br s, 1H), 1.14 (d, 3H), 0.87 (s, 3H). LRMS(Electrospray, positive): Da/e 393.2 (m+1).

EXAMPLE 47

R¹=2-(N-Methyl)benzimidazole; R³=CO₂CH₃

Methyl3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-benzimidazol-2-yloxy-4-methoxyphenyl)-3-methylpyrroli-dinecarboxylate

Prepared from Intermediate 74 via the K₂CO₃ etherification procedure ofExample 43 with 2-chloro-N-methylbenzimidazole.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.50 (d, 1H), 7.29-7.10(m, 5H), 6.95 (d, 1H), 3.80-3.66 (m, 13H), 3.57 (t, 1H) 7 3.29 (d,0.5H), 3.20 (d, 0.5H), 2.04 (br s, 1H), 1.13 (t, 3H), 0.77 (s, 3H). LRMS(Electrospray, positive): Da/e 440.2 (m+1).

EXAMPLE 48

R¹=2-(N-Methyl)benzimidazole; R³=CO₂CH₃: Diastereomer

Methyl3-((1S)-1-Hydroxyethyl)(3S,4S)-4-(3-benzimidazol-2-yloxy-4-methoxyphenyl)-3-methylpyrroli-dinecarboxylate

Prepared from the (1S)-carbinol isomer Intermediate 75 via the K₂CO₃etherification procedure of Example 43 using2-chloro-1-methyl-1H-benzimidazole. ¹H NMR (400 MHz, CDCl₃, mixture ofrotomers) δ: 7.50 (d, 1H), 7.50 (d, 1H), 7.30-7.09 (m, 5H), 6.96 (d,1H), 3.87-3.63 (m, 12H), 3.40-3.21 (m, 3H), 1.15 (d, 3H), 0.91 (s, 3H).LRMS (Electrospray, positive): Da/e 440.2 (m+1).

EXAMPLE 49

R¹=CH₂CH₂CH₂Ph; R³=CO₂CH₃

Methyl3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylpropoxy)phenyl]-3-methylpyrrolidinecarboxylate

Prepared from Intermediate 74 via the K₂CO₃, etherification procedure ofExample 43 using 3-phenylpropyl chloride.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.35-7.17 (m, 5H),6.85-6.77 (m, 3H), 4.02 (dt, 2H), 3.90-3.52 (m, 11H), 3.30 (d, 0.5H),3.21 (d, 0.5H), 2.82 (t, 2H), 2.14 (p, 2H), 1.54 (br s, 0.5H), 1.49 (brs, 0.5H), 1.13 (t, 3H), 0.72 (s, 3H).

EXAMPLE 50

R¹=CH₂CH₂CH₂Ph; R³=CO₂CH₃, Other Carbinol Diastereomer

Methyl3-((1S)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylpropoxy)phenyl]-3-methylpyrrolidinecarboxylate

Prepared from the (1S)-carbinol isomer Intermediate 75 via the K₂CO₃etherification procedure of Example 43 using the (1S)-carbinol isomer ofIntermediate 75.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.33-7.19 (m, 5H),6.84-6.78 (m, 2H), 6.72 (br s, 1H), 4.01 (t, 2H), 3.90-3.56 (m, 9H),3.34-3.23 (m, 3H), 2.82 (t, 2H), 2.15 (p, 2H), 1.11 (d, 3H), 0.89 (s,3H).

EXAMPLE 51

R¹=CH₂CH₂CH₂CH₂Ph; R³=CO₂CH₃

Methyl3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenylbutoxy)phenyl]-3-methylpyrrolidinecarboxylate

Prepared from Intermediate 74 via the K₂CO₃ etherificaiton procedure ofExample 43 using 1-chloro-4-phenylbutane.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.32-7.15 (m, 5H),6.84-6.74 (m, 3H), 4.00 (t, 2H), 3.89-3.51 (m, 11H), 3.30 (d, 0.5H),3.22 (d, 0.5H), 2.69 (t, 2H), 1.90-1.79 (m, 4H), 1.41 (dd, 1H), 1.13 (t,3H), 0.73 (s, 3H).

EXAMPLE 52

R¹=CH₂CH₂CH₂CH₂Ph; R³=CO₂CH₃, Other Carbinol Diastereomer

Methyl3-((1S)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenylbutoxy)phenyl]-3-methylpyrrolidinecarboxylate

Prepared from Intermediate 74 via the K₂CO₃ etherification procedure ofExample 43 using 1-chloro-5-phenylpentane.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.32-7.16 (m, 5H),6.83-6.70 (m, 3H), 3.99 (t, 2H), 3.90-3.58 (m, 9H), 3.34-3.21 (m, 3H),2.69 (t, 2H), 1.90-1.77 (m, 4H), 1.45 (br s, 1H), 1.12 (d, 3H), 0.90 (s,3H). LRMS (Electrospray, positive): Da/e 442.4 (m+1).

EXAMPLE 53

R¹=CH₂CH₂Ph; R³=Co₂CH₃

Methyl3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(2-phenylethoxy)phenyl]-3-methylpyrrolidinecarboxylate

Prepared from Intermediate 74 via the K₂CO₃ etherification procedure ofExample 43 using 2-phenethyl bromide.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.39-7.23 (m, 5H),6.84-6.78 (m, 3H),4.20 (t, 2H), 3.87-3.52 (m, 11H), 3.30 (d, 0.5H), 3.21(d, 0.5H), 3.15 (t, 2H), 1.13 (t, 3H), 0.73 (s, 3H). LRMS (Electrospray,positive): Da/e 414.3 (m+1).

EXAMPLE 54

R¹=CH₂CH₂Ph; R³=CO₂CH₃, Other Carbinol Diastereomer

Methyl3-((1S)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(2-phenylethoxy)phenyl]-3-methylpyrrolidinecarboxylate

Prepared from the (1S)-carbinol isomer Intermediate 75 via the K₂CO₃etherification procedure of Example 43.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.34-7.24 (m, 5H), 6.83(d, 1H), 6.79 (dd, 1H), 6.73 (br s, 1H), 4.18 (t, 2H), 3.89-3.56 (m,9H), 3.31-3.20 (m, 3H), 3.15 (t, 2H), 1.11 (d, 3H), 0.89 (s, 3H).

EXAMPLE 55

R¹=C₅H₉; R³=CH₂-2-Pyridyl

(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-(2-pyridylmethyl)pyrrolidin-3-yl]ethan-1-ol

Reductive Amination Procedure

To a stirred solution of Intermediate 68 (32 mg, 0.1 mmol) and pyridine2-carboxaldehyde (10 mL, 0.1 μmol) in dry 1,2-dichloroethane (0.3 mL)was added sodium triacetoxyborohydride (30 mg, 0.14 mmol) under anitrogen atmosphere at room temperature. After stirring for 3 hours, thereaction was quenched with saturated aqueous NaHCO₃ (0.1 mL) and stirredfor 5 minutes. The reaction was diluted with EtOAc (20 mL), washed withsaturated aqueous NaHCO₃ (20 mL), and brine (20 mL), then dried (MgSO₄),filtered, and concentrated in vacuo to provide Example 55 as a yellowoil (40.4 mg, 98%).

¹H NMR (400 MHz, CDCl₃) δ: 8.54 (ddd, 1H), 7.68 (dt, 1H), 7.43 (d, 1H),7.18 (ddd, 1H), 6.79-6.73 (m, 3H), 4.75 (c, 1H), 3.89-3.77 (m, 5H), 3.69(q, 1H), 3.59 (t, 1H), 3.33 (t, 1H), 3.15 (d, 1H), 2.70 (t, 1H), 2.21(d, 1H), 1.92-1.80 (m, 6H), 1.64-1.57 (m, 2H), 1.14 (d, 3H), 0.50, 3H).LRMS (Electrospray, positive): Da/e 411.4 (m+1).

EXAMPLE 56

R¹=C₅H₉; R³=CH₂-3-Pyridyl

(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-(3-pyridylmethyl)pyrrolidin-3-yl]ethan-1-ol

Prepared from Intermediate 68 via the reductive amination procedure ofExample 55 using pyridine-3-carboxaldehyde.

¹H NMR (400 MHz, CDCl₃) δ: 8.54 (d, 1H), 8.51 (dd, 1H), 7.68 (d, 1H),7.26 (dd, 1H), 6.78-6.71 (m, 3H), 4.74 (c, 1H), 3.86-3.78 (m, 4H), 3.68(q, 1H), 3.64 (d, 1H), 3.53 (t, 1H), 3.22 (t, 1H), 3.05 (d, 1H), 2.62(t, 1H), 2.14 (d, 1H), 1.92-1.78 (m, 6H), 1.64-1.56 (m, 2H), 1.12 (d,3H), 0.50 (s, 3H). LRMS (Electrospray, positive): Da/e 411.4 (m+1).

EXAMPLE 57

R¹=C₅H₉; R³=CH₂-4-Pyridyl

(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-(4-pyridylmethyl)pyrrolidin-3-yl]ethan-1-ol

Prepared from Intermediate 68 via the reductive amination procedure ofExample 55 using pyridine-4-carboxaldehyde.

¹H NMR (400 MHz, CDCl₃) δ: 8.54 (d, 2H), 7.27 (d, 2H), 6.79-6.72 (m,3H), 4.74 (c, 1H), 3.86-3.74 (m, 4H), 3.70 (q, 1H), 3.64 (d, 1H), 3.55(t, 1H), 3.23 (t, 1H), 3.06 (d, 1H), 2.64 (t, 1H), 2.15 (d, 1H),1.92-1.80 (m, 6H), 1.65-1.58 (m, 2H), 1.14 (d, 3H), 0.52 (s, 3H). LRMS(Electrospray, positive): Da/e 411.4 (m+1).

EXAMPLE 58

R¹=C₅H₉; R³=CH₂CH₂CO₂CH₂Ph

Phenylmethyl 3-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]propanoate

To a stirred solution of benzyl acrylate (19.4 mg, 0.12 mmol) in dry DMF(0.1 mL) was added Intermediate 68 (12.8 mg, 0.04 mmol) and powderedK₂CO₃ (26.5 mg, 0.18 mmol) under a nitrogen atmosphere. The resultingmixture was allowed to stir at 80° C. for 16 hours, then allowed to coolto room temperature. The reaction was diluted with CH₂Cl₂ (20 mL),washed with water, saturated aqueous NaHCO₃, and brine, then dried(Na₂SO₄), filtered, and concentrated in vacuo. The residue was purifiedvia flash chromatography (2:1 EtOAc:hexanes on silica gel) to provideExample 58 (11.7 mg, 60%).

¹H NMR (400 MHz, CDCl₃) δ: 7.37-7.31 (m, 5H), 6.81-6.72 (m, 3H), 5.14(q, 2H), 4.76 (c, 1H), 3.87-3.81 (m, 4H), 3.65 (q, 1H), 3.54 (t, 1H),3.31 (t, 1H) 3.15 (d, 1H), 2.82 (dt, 2H), 2.62-2.54 (m, 3H), 2.08 (d,1H), 1.91-1.81 (m, 6H), 1.66-1.56 (m, 2H), 1.15 (d, 3H), 0.48 (s, 3H).LRMS (Electrospray, positive): Da/e 482.3 (m+1).

EXAMPLE 59

R¹=C₅H₉; R³=CH₂CH₂CO₂H

3-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]propanoicAcid

Prepared from Example 58 via the debenzylation procedure of Intermediate31.

¹H NMR (400 MHz, CDCl₃) δ: 6.82-6.71 (m, 3H), 4.90 (c, 1H), 4.06-3.15(m, 11H), 2.73 (br s, 2H), 1.91-1.74 (m, 6H), 1.63-1.53 (m, 2H), 1.14(d, 3H), 0.68 (s, 3H).

EXAMPLE 60

R¹=C₅H₉; R³=CH₂CO₂CH₂Ph

Phenylmethyl2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrroli-dinyl]acetate

Prepared from Intermediate 68 via the Hunig's base mediated couplingprocedure of Intermediate 74 using benzyl bromoacetate.

¹H NMR (400 MHz, CDCl₃) δ: 7.41-7.32 (m, 5H), 6.82-6.73 (m, 3H), 5.18(q, 2H), 4.77 (c, 1H), 3.82 (s, 3H), 3.68 (q, 1H), 3.59 (t, 1H), 3.52(d, 1H), 3.36-3.30 (m, 2H), 3.24 (d, 1H), 2.88 (t, 1H), 2.31 (d, 1H),1.93-1.80 (m, 6H), 1.65-1.56 (m, 2H), 1.16 (d, 3H), 0.53 (s, 3H) LRMS(Electrospray, positive): Da/e 468.3 (m+1).

EXAMPLE 61

R¹=C₅H₉; R³=CH₂CO₂H

2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]aceticAcid

Prepared from Example 60 via debenzylation procedure of Intermediate 31.

¹H NMR (400 MHz, CDCl₃) δ: 6.77-6.68 (m, 3H), 5.56 (br s, 1H), 4.77 (c,1H), 3.99-3.85 (m, 4H), 3.82-3.59 (m, 7H), 2.88 (br s, 1H), 1.91-1.75(m, 6H), 1.59-1.51 (m, 2H), 11.1 (d, 3H), 0.67 (s, 3H). LRMS(Electrospray, negative): Da/e 376.2 (m−1).

EXAMPLE 62

R¹=C₅H₉; R³=COCH(OAc)Ph

2-[(3R)-3-((1R)-1-Hydroxyethyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-1-phenylethylAcetate

Prepared from Intermediate 68 (104 mg, 0.33 mmol) and O-acetyl mandelicacid chloride (75 μL, 0.33 mmol) by the acylation procedure of Example 7to give Example 62 (149 mg, 100%).

¹H-NMR (400 MHz, CDCl₃) δ: 7.60-7.37 (m, 5H), 6.82-6.70 (m, 3H), 6.08(m, 1H), 4.76 (m, 1H), 4.05-3.32 rm, 7H), 3.81 (s, 3H), 2.20 (s, 3H),1.95-1.53 (br m, 5H), 1.13 and 0.51 (doublets, 3H, rotomers), 0.79 and0.41 (singlets, 3H, rotomers).

EXAMPLE 63

R¹=C₅H₉; R³=COCH(OH)Ph

1-[(3R)-3-((1R)-1-Hydroxyethyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxy-2-phenylethan-1-one

Prepared from Example 62 by the LiOH hydrolysis procedure ofIntermediate 5 to provide Example 63 as a white foam (99 mg, 66%).

¹H-NMR (400 MHz, CDCl₃) δ: 7.41-7.26 (m, 5H), 6.80-6.41 (m, 3H),5.16-5.07 (m, 1H), 4.75-4.54 (multiplets, 1H, rotomers anddiastereomers), 4.06-2.80 (m, 7H), 3.81 and 3.79 and 3.78 (singlets, 3H,rotomers and diastereomers), 1.95-1.55 (br m, 5H), 1.15 and 1.02(doublets, 3H, rotomers), 0.77 and 0.75 and 0.46 and 0.38 (singlets, 3H,rotomers and diastereomers). LRMS (Electrospray, positive): Da/e 454.5(m+1).

EXAMPLE 64

R¹=C₅H₉; R³=COCH₂OCH₂Ph

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(phenylmethoxy)ethan-1-one

Prepared from Intermediate 68 (176 mg, 0.574 mmol) by the Hunig's baseprocedure of Intermediate 74 using benzyloxyacetyl chloride (31 μL, 0.22mmol, 2 eq), yielding a clear, colorless oil (79 mg, 29%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.33-7.28 (m, 5H),6.77-6.73 (m, 3H), 4.73-4.71 (m, 1H), 4.65-4.64 (m, 2H), 4.14-3.19 (c,12H), 2.07-1.56 (m, 8H), 1.16-1.09 (dd, 3H), 0.72 (s, 3H).

EXAMPLE 65

R¹=C₅H₉; R³=COCH₂OH

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyethan-1-one

Prepared from Example 64 by the debenzylation procedure of Intermediate31 yielding a white solid (47 mg, 73%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.82-6.76 (m, 3H),4.75-4.73 (m, 1H), 4.15-3.04 (c, 12H), 1.92-1.61 (m, 9H), 1.27-1.24 (dd,3H), 0.76 (s, 3H). LRMS (Electrospray, positive): Da/e 378.2 (m+1).

EXAMPLE 66

R¹=C₅H₉; R³=(S)—COCH(OAc)CH₃

2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl)(1S)-1-methyl-2-oxoethylAcetate

Prepared from Intermediate 68 (106 mg, 0.330 mmol) by the acylationprocedure of Example 7 using (S)-(−)-2-acetoxypropionyl chloride (84 μL,0.66 mmol, 2 eq), yielding a clear, colorless oil that was not purifiedfurther.

EXAMPLE 67

R¹=C₅H₉; R³=(S)-COCH(OH)CH₃

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-hydroxypropan-1-one

The crude compound of Example 66 was deprotected by the LiOH procedureof Intermediate 5 to give Example 67 as a white solid (22 mg, 17% fortwo steps).

¹H NMR (400 MHz, CDCl₃) δ: 6.82-6.76 (m, 3H), 4.75-4.73 (m, 1H),4.38-4.35 (m, 1H), 3.88-3.55 (c, 9H), 3.39-3.25 (dd, 1H), 1.92-1.58 (m,9H), 1.41-1.36 (dd, 3H), 1.18-1.14 (dd, 3H), 0.77-0.76 (d, 3H). LRMS(Electrospray, positive): Da/e 392.3 (m+1).

EXAMPLE 68

R¹=C₅H₉; R³=CO(CH₂CH₂)OAc

{[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]carbonyl}-cyclopropylAcetate

Intermediate 68 (97.6 mg, 0.306 mmol) was acylated by the acylationprocedure of Example 7 using 2-acetoxy-2-cyclopropanethanoyl chloride(99 mg, 0.61 mmol, 2 eq), yielding a clear, colorless oil (77 mg, 56%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.78-6.71 (m, 3H),4.72-4.71 (m, 1H), 3.80-3.36 (c, 10H), 2.08 (s, 3H), 1.90-1.50 (m, 11H),1.16-1.11 (d, 3H), 0.96 (br s, 1H), 1.18-1.14 (dd, 3H), 0.70 (s, 3H).

EXAMPLE 69

R¹=C₅H₉; R³=CO(CH₂CH₂)OH

3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinylhydroxycyclopropyl Ketone

The compound of Example 68 (77 mg) was hydrolyzed by the LiOH procedureof Intermediate 5 to give Example 69 as a white solid (34 mg, 44% fortwo steps).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.80-6.75 (m, 3H),4.74-3.33 (c, 10H), 2.30 (br s, 1H), 1.93-1.56 (m, 8H), 1.37-0.89 (m,8H), 0.74-0.72 (d, 3H). LRMS (Electrospray, positive): Da/e 404.4 (m+1).

EXAMPLE 70

R¹=C₅H₉; R³=COCH (OAc)(CH₃)CH₃

2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1,1-dimethyl-2-oxoethylAcetate

Intermediate 68 (124 mg, 0.0.389 mmol) was acylated by the acylationprocedure of Example 7 using (+)-2-acetoxy-2-methylpropionyl chloride(11 μL, 0.78 mmol, 2 eq.). The resulting oil was not purified futher.

EXAMPLE 71

R¹=C₅H₉; R³=COCH(OH)(CH₃)CH₃

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxy-2-methylpropan-1-one

The crude product of Example 70 was converted by the LiOH hydrolysisprocedure of Intermediate 5 to the give Example 71 as a white solid (47mg, 30%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.79-6.75 (m, 3H), 4.75(br s, 1H), 4.49 (br s, 1H), 3.91-3.48 (c, 10H), 1.90-1.46 (m, 14H),1.18-1.14 (dd, 3H), 0.77-0.74 (d, 3H). LRMS (Electrospray, positive):Da/e 406.3 (m+1).

EXAMPLE 72

¹R=C₅H₉; R³=COCO₂CH₃

Methyl2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoacetate

Intermediate 68 (57.5 mg, 0.180 mmol) was converted by the DIEAprocedure of Intermediate 32 using methyl oxalyl chloride to yieldExample 72 as a clear, colorless oil (26.8 mg, 36%).

¹H NMR (400 MHz, CDCl₃) δ: 6.81-6.77 (m, 3H), 4.75-4.74 (m, 1H),4.12-3.45 (c, 13H), 1.91-1.52 (m, 8H), 1.18-1.13 (dd, 3H), 0.78-0.75 (d,3H). LRMS (Electrospray, positive): Da/e 406.4 (m+1).

EXAMPLE 73

R¹=C₅H₉; R³=COCO₂H

2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-aceticAcid

Example 72 (46.8 mg, 0.116 mmol) was converted by the LiOH procedure ofIntermediate 5 to give Example 73 as a clear, colorless film (34 mg,76%).

¹H NMR (400 MHz, CDCl₃) δ: 6.82-6.76 (m, 3H), 4.75-4.73 (m, 1H),4.43-3.49 (c, 10H), 1.92-1.58 (m, 8H), 1.19-1.16 (dd, 3H), 0.78-0.76 (d,3H). LRMS (Electrospray, negative): Da/e 390.2 (m−1).

EXAMPLE 74

R¹=C₅H₉; R³=COCONH₂

2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-acetamide

Example 72 (7.1 mg, 0.014 mmol) was dissolved in THF (0.5 mL), NH₄OH(0.5 mL) was added, and the apparatus was sealed and stirred for 2 hoursat room temperature. TLC (1:1 EtOAc:hexanes) showed complete consumptionof starting material. The reaction was diluted with EtOAc (20 mL), andthe organic layers were washed with brine (2×15 mL). The organic layerwas dried over Na₂SO₄ and concentrated in vacuo to give a clear,colorless oil (6.6 mg, 117%).

¹H NMR (400 MHz, CDCl₃) δ: 7.36 (br s, 1H), 6.82-6.79 (m, 3H), 5.53 (brs, 1H), 4.76-4.75 (m, 1H), 4.44-3.47 (c, 10H), 1.92-1.58 (m, 8H),1.18-1.17 (d, 3H), 0.78-0.74 (d, 3H). LRMS (Electrospray, negative):Da/e 389.1 (m−1).

EXAMPLE 75

R¹=PhC≡CCH₂; R³=COCONH₂

2-{(3S,4S)-3-((R)-1-Hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)-phenyl]-3-methylpyrrolidin-1-yl}-2-oxo-acetamide

Prepared by acylation of Intermediate 73 with methyl oxalyl chloride bythe DIEA procedure of Intermediate 32, removal of the t-butyl group bythe procedure of Intermediate 72, O-alkylation with Intermediate 90 bythe K₂CO₃ etherification procedure of Example 43, and amidation by theprocedure of Example 74.

¹H NMR data δ: 7.28-7.42 (m, 5H); 7.08 (sd, 1H); 6.83-6.87 (m, 2H); 5.45(bs, 1H); 5.0 (s, 2H); 4.42-4.48 (2d, 0.5H); 4.26 (t, 0.5H); 3.72-4.01(m, 3.5H); 3.89 (s, 3H); 3.50-3.70 (m, 1H); 3.44 (d, 0.5H); 0.96-0.99(dd, 3H); 0.71 (d, 3H).

EXAMPLE 76

R¹=4-CF₃PhC≡CCH₂; R³=COCONH₂

2-((3S,4S)-3-((R)-1-Hydroxyethyl)-4-{4-methoxy-3-[3-(4-trifluoromethyl-phenyl)prop-2-ynyloxy]-phenyl}-3-methylpyrrolidin-1-yl)-2-oxo-acetamide

Prepared as described in Example 75, using Intermediate 92 as theO-alkylating reagent.

¹H NMR data δ: 7.50-7.61 (m, 4H); 7.04 (s, 1H); 6.85-6.91 (m, 2H); 5.69(bs, 1H); 5.00 (s, 2H); 4.42-4.49 (2d, 0.5H); 4.26 (t, 0.5H); 3.69-4.07(m, 5H); 3.90 (s, 3H); 3.45-3.58 (m, 1H); 1.04-1.07 (dd, 3H); 0.73 (d,3H)

EXAMPLE 77

R¹=4-FPhOCH₂CH₂CH₂; R³=COCONH₂

2-[(3S,4S)-4-{3-[3-(4-Fluorophenoxy)propoxy]-4-methoxyphenyl}-3-((R)-1-hydroxyethyl)-3-methoxyphenyl-1-yl]-2-oxo-acetamide

Prepared as described in Example 75, using1-(3-chloropropoxy)-4-fluorobenzene as the alkylating reagent.

¹H NMR data δ: 6.93-6.99 (m, 2H); 6.82-6.88 (m, 5); 5.44 (s, 1H); 4.40(dd, 0.5H); 4.14-4.22(m, 5H);3.83 (s, 3H); 3.69-4.04 (m, 5H); 3.56 (d,0.5H); 2.28 (quint, 2H); 1.16 (dd, 3H): 0.75 (d, 3H).

EXAMPLE 78

R¹=CH₂C₃H₅; R³=COCONH₂

2-[(3S,4S)-4-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-oxo-acetamide

Prepared as described in Example 75, using cyclopropylmethyl bromide asthe alkylating reagent.

¹H NMR data δ: 6.80-6.81 (m, 3H); 5.50 (bs, 1H); 4.40 (2d, 0.5H); 4.23(t, 0.5H); 3.68-4.05 (m, 7H); 3.84 (s, 3H); 1.40 (t, 1H); 1.17 (sd, 3H);0.76 (d, 3H); 0.61-0.67 (m, 2H); 0.33-0.38 (m, 2H).

EXAMPLE 79

R¹=2-Indanyl; R³=COCONH₂

2-{(3S,4S)-3-((R)-1-Hydroxyethyl)-4-[3-(indan-2-yloxy)-4-methoxyphenyl]-3-methylpyrrolidin-1-yl}-2-oxo-acetamide

Prepared as described in Example 75, using 2-bromoindane as thealkylating reagent.

¹H NMR data δ: 7.16-7.24 (m, 4H); 6.84-6.87 (m, 3H); 5.51 (s, 1H);5.17-5.20 (m, 1H); 4.42-4.5 (2d, 0.5H); 4.24 (t, 0.5H); 3.60-4.06 (m,6H); 3.81 (s, 3H); 3.20-3.40 (m, 4H); 1.20 (sd, 3H); 0.78 (d, 3H).

EXAMPLE 80

¹R=C₅H₉; R³=COCONHCH₃

2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-N-methyl-2-oxoacetamide

Example 72 (17.3 mg, 0.0427 mmol) was dissolved in THF (0.8 mL).Methylamine (40% in water, 0.5 mL) was added, and the apparatus wassealed and stirred for 1 hour at room temperature. TLC (3:1EtOAc:hexanes) showed complete consumption of starting material. Thereaction was diluted with EtOAc (20 mL), and the organic layers werewashed with brine (2×15 mL). The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to give a clear, colorless oil (16.9 mg, 97%).

¹H NMR (400 MHz, CDCl₃) δ: 7.59 (br s, 1H), 6.80-6.79 (m, 3H), 4.75-4.73(m, 1H), 4.47-3.46 (c, 10H), 2.89-2.87 (dd, 3H), 1.91-1.57 (m, 8H),1.18-1.16 (dd, 3H), 0.76-0.73 (d, 3H). LRMS (Electrospray, positive):Da/e 405.1 (m+1).

EXAMPLE 81

R¹=C₅H₉; R³=COCO-piperidine

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-piperidylethane-1,2-dione

Example 72 (25.4 mg, 0.0626 mmol) was dissolved in THF (0.8 mL).Piperidine (213 μL, 2.15 mmol, 34 eq.) was added, and the apparatus wassealed and heated at 53° C. for 12 hours. TLC (100% EtOAc) showed asmall amount of product formation. The reaction was diluted with EtOAc(20 mL), the organic layers were washed with 2N HCl (2×15 mL), 1N NaOH(15 mL), and brine (2×15 mL). The organic layer was dried over Na₂SO₄and concentrated in vacuo to give a clear, colorless oil (1.2 mg, 4%).

¹H NMR (400 MHz, CDCl₃) δ: 6.82-6.76 (m, 3H), 4.75 (m, 1H), 4.01-3.27(c, 14H), 1.89-1.59 (m, 14H), 1.18-1.13 (dd, 3H), 0.78-0.74 (d, 3H).

EXAMPLE 82

R¹=C₅H₉; R³=COCONHC₅H₉

2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-N-cyclopentyl-2-oxoacetamide

Example 72 (20.9 mg, 0.0515 mmol) was dissolved in THF (0.8 mL).Cyclopentylamine (211 μL, 2.13 mmol, 41 eq.) was added, and the reactionwas stirred at room temperature for 42 hours. The reaction was dilutedwith EtOAc (20 mL), and the organic layers were washed with 2N HCl (2×15mL), 1N NaOH (15 mL), and brine (2×15 mL). The organic layer was driedover Na₂SO₄ and concentrated in vacuo. The resulting oil was purified bysilica chromatography (100% EtOAc) to give a clear, colorless oil (14.0mg, 59%).

¹H NMR (400 MHz, CDCl₃) δ: 7.57-7.53 (br s, 1H), 6.8-6.78 (m, 3H),4.76-4.73 (br s, 1H), 4.48-3.44 (c, 9H), 2.04-1.48 (m, 18H), 1.18-1.16(d, 3H), 0.77-0.73 (d, 3H) LRMS (Electrospray, negative): Da/e 457.2(m−1).

EXAMPLE 83

R¹=C₅H₉; R³=COCONHCH₂Ph

2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-N-benzylacetamide

Example 83 was prepared by the method of Example 82 using benzylamine togive a clear, colorless oil (9.4 mg, 47%).

¹H NMR (400 MHz, CDCl₃) δ: 7.96-7.92 (br s, 1H), 7.36-7.25 (m, 3H), 4.75(br s, 1H), 4.49-4.47 (d, 2H), 4.28-3.46 (c, 9H), 1.93-1.61 (m, 8H),1.19-1.16 (dd, 3H), 0.78-0.74 (d, 3H). LRMS (Electrospray, positive):Da/e 481.4 (m+1).

EXAMPLE 84

R¹=C₅H₉; R³=(R)—COCH(C₄H₉)NHCO₂CH₂Ph

N-{(1R)-2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-butyl-2-oxoethyl}(phenylmethoxy)carboxamide

Intermediate 68 (39.5 mg, 0.129 mmol) was converted by the DIEAprocedure of Intermediate 32 to yield a clear, colorless oil (59.0 mg,80%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.36-7.26(m, 5H),6.82-6.71 (m, 3H), 5.71-5.68 (dd, 1H), 5.12-5.06 (m, 2H), 4.73 (m, 1H),4.49-4.47 (m, 1H), 4.12-2.58 (c, 8H), 2.03-1.25 (m, 16H), 1.16-1.14 (dd,3H), 0.92-0.84 (m, 3H), 0.73-0.72 (d, 3H).

EXAMPLE 85

R¹=C₅H₉; R³=(R)—COCH(NH₂)C₄H₉

(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-aminohexan-1-one

Example 84 (59 mg, 0.10 mmol) was converted by the debenzylationprocedure of Intermediate 31 to give Example 85 as a white powder (43mg, 95%).

¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 6.90-6.83 (m, 3H),3.85-3.30 (c, 10H), 2.00-1.37 (m, 14H), 1.14-1.11 (dd, 3H), 1.10-0.92(dt, 3H), 0.77 (s, 3H). LRMS (Electrospray, positive): Da/e 433.5 (m+1).

EXAMPLE 86

R¹=C₅H₉; R³=(R)—COCH (i-Pr) NHCO₂CH₂Ph

N-{(1R)-2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-(methylethyl)-2-oxoethyl}(phenylmethoxy)carboxamide

Intermediate 68 (43.7 mg, 0.143 mmol) was acylated by the Hunig's basemethod of Intermediate 74 using Z-D-Val-OSu (54.6 mg, 0.15 mmol, 1.1eq), yielding a clear, colorless oil (38.9 mg, 49%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.36-7.33 (m, 5H),6.80-6.71 (m, 3H), 5.62-5.59 (d, 1H), 5.10-5.06 (m, 2H), 5.84-5.72 (m,1H), 4.12-2.68 (c, 10H), 2.03-1.52 (m, 9H), 1.18-1.14 (dd, 3H) 1.04-0.92(m, 7H), 0.73-0.70 (d, 3H).

EXAMPLE 87

R¹=C₅H₉; R³=(R)—COCH(i-Pr)NH₂

(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-amino-3-methylbutan-1-one

Example 86 (38.9 mg, 0.070 mmol) was converted by the debenzylationprocedure of Intermediate 31 to give Example 87 as clear solid (26 mg,88%).

¹H NMR (400 MHz, CDCl₃) δ: 6.42-6.33 (m, 3H), 4.36 (m, 1H), 3.62-2.80(c, 10H), 2.81-2.68 (m, 1H), 1.42-1.08 (m, 9H), 0.78-0.65 (m, 9H), 0.24(s, 3H). LRMS (Electrospray, positive): Da/e 419.5 (m+1).

EXAMPLE 88

R¹=C₅H₉; R³=(S)—COCH(OAc)C₆H₁₁

2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-1-cyclohexyl-2-oxoethylAcetate

Intermediate 68 (41.2 mg, 0.129 mmol) was acylated by the Hunig's baseprocedure of Intermediate 74 using (S)-(+)-acetoxyhexahydromandelic acidchloride (625 μL, 0.4121 M in CH₂Cl₂, 2 eq) to give Example 88 as aclear, colorless oil (40.5 mg, 63%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.78-6.77 (m, 3H),4.84-4.72 (m, 2H), 4.12-3.11 (m, 9H), 2.10 (d, 3H), 2.02-1.68 (m, 1 5H),1.38-0.99 (m, 10H), 0.81-0.74 (d, 3H).

EXAMPLE 89

R¹=C₅H₉; R³=(S)—COCH(OH)C₆H₁₁

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-cyclohexyl-2-hydroxyethan-1-one

Example 88 (40.5 mg, 0.0807 mmol) was converted by the LiOH hydrolysisprocedure of Intermediate 5 to afford Example 89 as a clear, colorlessoil (26.9 mg, 72%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.80-6.78(m, 3H), 4.73(m, 1H), 4.14-4.06 (m, 1H), 3.83-2.99 (c, 9H), 1.91-1.36 (m, 1 7H),1.35-1.11 (m, 7H), 0.79-0.78 (d, 3H). LRMS (Electrospray, positive):Da/e 460.3 (m+1).

EXAMPLE 90

R¹=C₅H₉; R³=(R)—COCH(OAc)C₆H₁₁

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2R)-2-cyclohexyl-2-acetoxyethan-1-one

Intermediate 68 (43.1 mg, 0.135 mmol) was converted by the Hunig's baseprocedure of Intermediate 74 using (R)-(−)-acetoxyhexahydromandelic acidchloride (368 μL, 0.734 M in CH₂Cl₂, 2 eq) to give a clear, colorlessoil (59.9 mg, 88%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.84-6.64(m, 3H),4.78-4.76 (m, 2H), 4.12-2.65 (c, 9H), 2.11 (d, 3H), 2.10-1.51 (m, 1 5H),1.38-0.98 (m, 10H), 0.73-0.65 (d, 3H).

EXAMPLE 91

R¹=C₅H₉; R³=(R)—COCH(OH)C₆H₁₁

(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-cyclohexyl-2-hydroxyethan-1-one

Example 90 (59.9 mg, 0.119 mmol) was converted by the LiOH hydrolysisprocedure of Intermediate 5 to give a clear, colorless film (46.6 mg,84%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.85-6.74 (m, 3H),4.79-4.72 (m, 1H), 4.13-4.07 (m, 1H), 3.87-3.01 (c, 9H), 1.96-1.34 (m, 17H), 1.34-1.08 (m, 7H), 0.78-0.77 (d, 3H). LRMS (Electrospray,positive): Da/e 460.4 (m+1).

EXAMPLE 92

R¹=C₅H₉; R³=(S)—COCH(C₄H₉)NHCO₂CH₂Ph

N-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-(1S)-1-butyl-2-oxoethyl}(phenylmethoxy)carboxamide

Intermediate 68 (40.6 mg, 0.125 mmol) was converted by the Hunig's baseprocedure of Intermediate 74 using Z-L-Nle-ONp (53 mg, 0.15 mmol, 1.1eq) to give Example 92 as a clear, colorless oil (50.4 mg, 71%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.36-7.25 (m, 5H),6.80-6.75 (m, 3H), 5.74-5.72 (dd, 1H), 5.10-5.06 (m, 2H), 4.74-4.53 (m,1H), 4.13 (m, 1H), 4.13-3.35 (c, 8H), 1.95-1.24 (m, 16H), 1.14-1.13 (d,3H), 0.93-0.87 (m, 3H), 0.74 (s, 3H).

EXAMPLE 93

R¹=C₅H₉; R³=(S)—COCH(C₄H₉) NH₂

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-aminohexan-1-one

Example 92 (50.4 mg, 0.0889 mmol) was subjected to the debenzylationprocedure of Intermediate 31 to give Example 93 as a white solid (31.7mg, 82%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.89-6.74 (m, 3H),4.83-4.75 (m, 1H), 4.40-3.32 (c, 10H), 1.99-1.68 (m, 14H), 1.14-1.12 (m,3H), 1.04-0.95 (d, 3H), 0.91-0.88 (d, 3H). LRMS (Electrospray,positive): Da/e 433.5 (m+1).

EXAMPLE 94

R¹=C₅H₉; R³=(R)—COCH(OAc)(CH₂)₃CH₃

(1R)-2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-butyl-2-oxoethylAcetate

Prepared from Intermediate 68 via the Hunig's base coupling procedure ofIntermediate 74 using (1R)-1-(chlorocarbonyl)pentyl acetate.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.81 (m, 2H), 6.79-6.69(m, 3H), 5.10-5.02 (m, 1H), 4.79-4.73 (m, 1H), 4.14-3.18 (c, 9H), 2.14(d, 3H), 1.94-1.76 (m, 8H), 1.53-1.34 (m, 4H), 1.20 (dd, 2H), 0.96-0.86(m, 3H), 0.74 (d, 3H).

EXAMPLE 95

R¹=C₅H₉; R³=(R)—COCH(OH)(CH₂)₃CH₃

(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyhexan-1-one

Example 94 (5 mg, 0.011 mmol) was hydrolyed by LiOH to yield Example 95(2.5 mg, 55%), as a clear film.

¹H NMR (Methanol-d₄, 400 MHz) δ: 6.91-6.80 (m, 3H), 4.34-4.28 (m, 1H),4.04-3.35 (c, 9H), 1.90-1.77 (m, 8H), 1.74-1.62 (m, 2H), 1.55-1.23 (m,4H), 1.12 (d, 3H), 0.97-0.87 (m, 3H), 0.74 (s, 3H). LRMS (Electrospray,positive): Da/e 434.2 (m+1).

EXAMPLE 96

R¹=C₅H₉; R³=(S)—COCH(NHCBZ)CH₂Ph

N-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-(1S)-2-oxo-1-benzylethyl}(phenylmethoxy)carboxamide

Prepared from Intermediate 68 via the Hunig's base acylation procedureof Intermediate 74 using the p-nitrophenylester ofN-CBZ-(S)-phenylalanine.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.41-7.26 (m, 10H),6.78-6.42 (m, 3H), 5.78-5.74 (m, 1H), 5.14-5.05 (m, 2H), 4.76-4.70 (m,2H), 3.81 (s, 3H), 3.75-2.66 (c, 10H), 1.94-1.80 (m, 6H), 1.65-1.57 (m,2H), 1.08-0.99 (dd, 3H), 0.64 and 0.33 (s, 3H). LRMS (Electrospray,positive): Da/e 601.2 (m+1).

EXAMPLE 97

R¹=C₅H₉; R³=(S)—COCH(NH₂)CH₂Ph

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-amino-3-phenylpropan-1-one

Prepared from Example 96 via the debenzylation procedure of Intermediate31.

¹H NMR (Methanol-d₄, 400 MHz, mixture of rotomers) δ: 7.47-7.31 (m, 5H),6.88-6.47 (m, 3H), 4.78-4.76 (m, 1H), 4.48-4.44 (m, 1H), 3.80-3.06 (c,13H), 1.88-1.80 (m, 6H), 1.67-1.64 (m, 2H), 1.02 (d, 3H), 0.75 and 0.34(s, 3H). LRMS (Electrospray, positive): Da/e 467.5 (m+1).

EXAMPLE 98

R¹=C₅H₉; R³=(R)—COCH(NHCBZ)CH₂Ph

N-{(1R)-2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-1-benzylethyl}(phenylmethoxy)carboxamide

Prepared from Intermediate 68 via the Hunig's base acylation procedureof Intermediate 74 using the p-nitrophenylester ofN-CBZ-(R)-phenylalanine.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.41-7.19 (m, 10H),6.77-6.46 (m, 3H), 5.70 (d, 1H), 5.14-5.04 (m, 2H), 4.76-4.69 (m, 2H),3.82 (s, 3H), 3.93-2.99 (c, 6H), 2,53 (d, 1H), 1.93-1.81 (m, 6H),1.62-1.56 (m, 2H), 1.06 (dd, 3H), 0.67 and 0.28 (s, 3H). LRMS(Electrospray, positive): Da/e 602.3 (m+1).

EXAMPLE 99

R¹=C₅H₉; R³=(R)—COCH(NH₂)CH₂Ph

(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-amino-3-phenylpropan-1-one

Prepared from Example 98 via the debenzylation procedure of Intermediate31.

¹H NMR (Methanol-d₄, 400 MHz, mixture of rotomers) δ: 7.42-7.26 (m, 5H),6.88-6.65 (m, 3H), 4.80-4.78 (m, 1H), 4.42-4.39 (m, 1H), 3.89-2.42 (c,13H), 1.89-1.79 (m, 6H), 1.64-1.62 (m, 2H), 0.99 (dd, 3H), 0.69 and 0.21(s, 3H). LRMS (Electrospray, positive): Da/e 467.0 (m+1).

EXAMPLE 100

R¹=CH₂C₃H₅; R³=COCH(OAc)C₄H₉

2-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxo-1-propylethylAcetate

Intermediate 67 (46 mg, 0.15 mmol) was converted by the Hunig's baseprocedure of Intermediate 74 using (±)-2-acetoxypropionyl chloride (29mg, 0.165 mmol) to afford Example 100 (36 mg, 54%).

¹H-NMR (400 MHz, CDCl₃) δ: 6.86-6.69 (m, 3H), 5.30-5.02 (m, 1H),4.17-4.00 (m, 1H), 3.82 (s, 3H), 3.82-3.18 (m, 5H), 3.08 and 2.97(singlets, 2H, rotomers), 2.13 and 2.11 (singlets, 3H, rotomers),1.95-1.23 (m, 5H), 1.20-1.14 (m, 2H), 1.00-0.92 (m, 3H), 0.76 and 0.72(doublets, 3H, rotomers), 0.62 (m, 2H), 0.36 (m, 2H).

EXAMPLE 101

R¹=CH₂C₃H₅; R³=COCH(OH)C₄H₉

1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxypentan-1-one

Example 100 (36 mg, 80 ρmol) was subjected to the LiOH hydrolysisprocedure of Intermediate 5 to provide Example 101 as a clear film (30mg, 90%).

¹H-NMR (400 MHz, CDCl₃) δ: 6.85-6.73 (m, 3H), 4.23 (m, 1H), 4.07-2.98(m, 6H), 3.83 (s, 3H), 1.71-1.23 (m, 5H), 1.16 (m, 3H), 0.96 (m, 3H),0.77 (s, 3H), 0.62 (m, 2H), 0.37 (m, 2H). LRMS (Electrospray, positive):Da/e 406.5 (m+1).

EXAMPLE 102

R¹=CH₂C₃H₅; R³=(S)—COC(CH₃)OCH₂Ph

1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-(phenylmethoxy)propan-1-one

Intermediate 67 (46 mg, 0.15 mmol) was converted by the Hunig's baseprocedure of Intermediate 74 using (2S)-2-(phenylmethoxy)propanoylchloride (59 mg, 0.3 mmol) to give Example 102 (54 mg, 77%).

¹H-NMR (400 MHz, CDCl₃) δ: 7.40-7.25 (m, 5H), 6.82-6.77 (m, 2H), 6.72(s, 1H), 4.63 (dd, 1H), 4.49 (dd, 1H), 4.22 (m, 1H), 3.98-3.38 (m, 8H),3.82 (s, 3H), 3.07 and 2.96 (singlets, 1H, rotomers), 1.43 (m, 3H), 1.31(m, 1H), 1.17 and 1.10 (doublets, 3H, rotomers), 0.72 and 0.70(singlets, 3H, rotomers), 0.62 (m, 2H), 0.37 (m, 2H).

EXAMPLE 103

R¹=CH₂C₃H₅; R³=(S)—COC(CH₃)OH

1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-(hydroxy)propan-1-one

Prepared from Example 102 (54 mg, 0.12 mmol) by the debenzylationprocedure of Intermediate 31 to give Example 103 as a clear oil (45 mg,100%).

1H-NMR (400 MHz, CDCl₃) δ: 6.84-6.73 (m, 3H), 4.44 (m, 1H), 4.06-3.16(m, 8H), 3.82 (s, 3H), 2.99 (d, 1H), 1.38 (m, 3H, rotomers), 1.30 (m,1H), 1.18 (m, 3H, rotomers), 0.78 and 0.76 (singlets, 3H, rotomers),0.62 (m, 2H), 0.36 (m, 2H). LRMS (Electrospray, positive): Da/e 378.7(m+1).

EXAMPLE 104

R¹=CH2C₃H₅; R³=(R)—COCH(t-Bu)NHCO₂t-Bu

N-((1R)-2-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-(tert-butyl)-2-oxoethyl)(tert-butoxy)carboxamide

Intermediate 67 (46 mg, 0.15 mmol) was converted by the EDCI couplingprocedure of Example 27 using Boc-D-t-butylglycine (35 mg, 0.15 mmol) toprovide Example 104 as a white foam (62 mg, 80%).

1H-NMR (400 MHz, CDCl₃) δ: 6.85-6.79 (m, 2H), 6.72-6.64 (m, 1H),4.36-4.00 (m, 3H, rotomers), 3.83 (s, 3H), 3.79 (d, 2H), 3.67-3.12 (m,4H, rotomers), 1.44 and 1.41 (singlets, 9H, rotomers), 1.32 (m, 1H),1.22-1.16 (m, 3H), 1.06 and 1.01 (singlets, 9H, rotomers), 1.02 (m, 3H),0.73 and 0.63 (singlets, 3H, rotomers), 0.61 (m, 2H), 0.36 (m, 2H).

EXAMPLE 105

R¹=CH₂C₃H5; R³=(R)—COCH(t-Bu) NH₂

(2R)-1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-amino-3,3-dimethylbutan-1-one

To a stirred solution of Example 104 (62 mg, 0.12 mmol) In CH₂Cl₂ (1.5mL) at room temperature in a capped flask was added trifluoroacetic acid(77 μL, 1 mmol). After stirring overnight, the reaction was concentratedin vacuo to provide a crude product that appeared to containtrifluoroacetate ester impurity. The crude product was dissolved in 3:2THF: H₂O (1.5 mL) at room temperature, and stirred in a capped flask andtreated with LiOH monohydrate (42 mg, 1 mmol). After 1 hour, the mixturewas partitioned between EtOAc (15 mL) and water (15 mL). The organiclayers were isolated, dried (MgSO₄) filtered, and concentrated in vacuoto provide Example 105 as a white foam (35 mg, 70%).

1H-NMR (400 MHz, CDCl₃) δ: 6.85-6.82 (m, 2H), 6.78-6.73 (m, 1H),4.01-3.30 (m, 9H), 3.83 (s, 3H), 1.13 and 1.12 (doublets, 3H, rotomers),1.0, and 1.02 (singlets, 9H, rotomers), 0.78 and 0.8 (singlets, 3H,rotomers), 0.63 (m, 2H), 0.37 (m, 2H). LRMS (Electrospray, positive):Da/e 419.4 (m+1).

EXAMPLE 106

R¹=H; R³=(R)—COCH(CH₂OCH₂Ph)NHCO₂t-Bu

N-{2-[(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1R)-2-oxo-1-[(phenylmethoxy)methyl]ethyl}(tert-butoxy)carboxamide

To a stirred solution of N-Boc-O-benzyl-D-serine (2.95 gm, 10 mmol) inTHF (50 mL) at −78° C. under a nitrogen blanket was added N-methylmorpholine (3.3 mL, 30 mmol) followed by isobutyl chloroformate (1.3 mL,10 mmol). After stirring for 30 minutes, a solution/suspension ofIntermediate 70 (2.51 gm, 10 mmol) in THF (50 mL) was added by cannula.The reaction was stirred For 2 hours at −78°C., then warmed to 0° C. for2 hours. The reaction then was partially concentrated by rotaryevaporator to approximately 25 mL, and partitioned between EtOAc (250mL) and 2N HCl (250 mL). The organic layers were washed with 2N HCl(2×250 mL), saturated NaHCO₃ (3×250 mL), and saturated NaCl (1×250 mL)The organic layers were dried (MgSO₄), filtered, and concentrated invacuo to provide Example 106 as a yellow oil (4.2 gm, 79%).

1H-NMR (400 MHz, CDCl₃) δ: 7.36-7.21 (m, 5H), 6.81-6.63 (m, 3H), 5.81(br s, 1H), 5.47 (m, 1H), 4.73 (m, 1H), 4.51 (m, 2H), 4.00-3.40 (m,83.83H), 3.84 and 3.82 (singlets, 3H, rotomers), 1.43 and 1.41(singlets, 9H, rotomers), 1.13 and 1.06 (doublets, 3H, rotomers), 0.95(m, 1H), 0.73 and .045 (singlets, 3H, rotomers).

EXAMPLE 107

R¹=CH₂C₃H₅; R³=(R)—COCH(CH₂OCH₂Ph) NHCO₂t-Bu

N-(2-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-2-oxo-1-[(phenylmethoxy)methyl]ethyl)-(tert-butoxy)carboxamide

To a stirred solution of Example 106 (4.2 gm, 7.9 mmol) in DMF (24 mL)at room temperature under a nitrogen blanket was added powdered K₂CO₃(5.45 gm, 39.5 mmol) followed by bromomethylcyclopropane (1.53 mL, 15.8mmol). The suspension was warmed to 65° C. for 4 hours, then treatedwith more bromomethylcyclopropane (1.53 mL, 15.8 mmol). The reaction wasstirred another 16 hours at 65° C., then cooled to room temperature andpartitioned between EtOAc (500 mL) and water (500 mL). The organiclayers were washed with water (3×500 mL) and saturated NaCl (1×500 mL),dried (MgSO₄), filtered, and concentrated in vacuo. The crude productwas divided into two batches, and chromatographed on a Biotage 40Mcolumn with 1/1 EtOAc/hexane to provide, after pooling and concentrationin vacuo of product containing fractions, Example 107 (2.11 gm, 46%). Ahigh R₅ dialkylated product was identified as a major impurity.

1H-NMR (400 MHz, CDCl₃) δ: 7.36-7.22 (m, 5H), 6.81-6.71 (m, 3H), 5.42(m, 1H), 4.73 (m, 1H), 4.51 (m, 2H), 4.04-3.44 (m, 10H), 3.83 and 3.81(singlets, 3H, rotomers), 1.42 and 1.43 (singlets, 9H, rotomers), 1.32(m, 1H), 1.16 and 1.06 (doublets, 3H, rotomers), 0.76 and 0.45(singlets, 3H, rotomers), 0.62 (m, 2H), 0.37 (m, 2H).

EXAMPLE 108

R¹=CH₂C₃H₅; R³=(R)—COCH(CH₂OH) NHCO₂t-Bu

N-(2-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1R)-1-(hydroxymethyl)-2-oxoethyl)(tert-butoxy)carboxamide

Example 107 (2.1 gm, 3.6 mmol) was subjected to the debenzylationprocedure of Intermediate 31 to afford Example 108 as a white foam (1.75gm, 100%).

1H-NMR (CDCl₃/CD₃OD, 400 MHz) δ: 6.83-6.71 (m, 3H), 5.70 (br d, 1H),4.55 (m, 1H), 4.09-3.38 (m, 10H), 3.83 (s, 3H), 1.44 (s, 9H), 1.33 (m,1H), 1.18 (m, 3H), 0.73 (d, 3H), 0.62 (m, 2H), 0.37 (m, 2H).

EXAMPLE 109

R¹=CH₂C₃H₅; R³=(R)—COCH(CH₂₀H) NH₂

1-{(3S,4S)-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropyl-methoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2R)-2-amino-3-hydroxypropan-1-onehydrochloride

To a stirred solution of Example 108 (1.75 gm, 3.6 mmol) in dioxane (16mL) at room temperature under a drying tube was added 4N HCl in dioxane(16 mL). The clear solution was stirred for 4 hours, then concentratedin vacuo to provide Example 109 as a tan foam (1.5 gm, 97%).

1H-NMR (400 MHz, CDCl₃) δ: 6.85-6.76 (m, 3H), 4.36 (m, 1H), 4.13-3.31(m, 10H), 3.84 (s, 3H), 1.29 (m, 1H), 1.17 and 1.12 (doublets, 3H,rotomers), 1.77 and 1.75 (singlets, 3H, rotomers), 0.62 (m, 2H), 0.36(m, 2H). LRMS (Electrospray, positive): Da/e 393.4 (m+1).

EXAMPLE 110

R¹=CH₂C₃H₅; R³=(S)—COCH(OAc)C₆H₁₁

2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-cyclohexyl-2-oxoethylAcetate

Intermediate 67 (91 mg, 0.6 mmol) was coupled by the Hunig's baseprocedure of Intermediate 74 using (S)-(+)-acetoxyhexahydromandelic acidchloride (100 μL, 4.98 M in CH₂Cl₂, 1.7 eq) to yield Example 110 as aclear, colorless oil (89 mg, 61%).

LRMS (Electrospray, positive): Da/e 488.6 (m+1).

EXAMPLE 111

R¹=CH₂C₃H₅; R³=(S)—COCH(OH)C₆H₁₁

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-cyclohexyl-2-hydroxyethan-1-one

Example 110 (89 mg, 0.18 mmol) was subjected to the LiOH hydrolysisprocedure of Intermediate 5 to afford Example 111 as a clear, colorlessfilm (44 mg, 54%).

¹NMR (400 MHz, CDCl₃) δ: 6.80-6.78 (m, 3H), 3.88-3.52 (c, 10H),3.34-3.26 (dd, 1H), 2.98 (d, 1H), 2.12 (br s, 1H), 1.77-1.10 (c, 16H),0.75-0.73 (d, 3H), 0.62-0.59 (m, 2H), 0.34-0.31 (m, 2H). LRMS(Electrospray, positive): Da/e 446.6 (m+1).

EXAMPLE 112

R¹=CH₂C₃H₅; R³=(R)—COCH(OAc)C₆H₁₁

(1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-cyclohexyl-2-oxoethylAcetate

Intermediate 67 (76 mg, 0.25 mmol) was coupled by the Hunig's baseprocedure of Intermediate 74 with (R)-(−)-acetoxyhexahydromandelic acidchloride (100 μL, 4.16 M in CH₂Cl₂, 1.7 eq) to give Example 112 as aclear, colorless oil (75 mg, 62%).

LRMS (Electrospray, positive): Da/e 488.7 (m+1).

EXAMPLE 113

R¹=CH₂C₃H₅; R³=(R)—COCH(OH)C₆H₁₁

(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-cyclohexyl-2-hydroxyethan-1-one

Example 112 (75 mg, 0.15 mmol) was subjected to the LiOH hydrolysisprocedure of Intermediate 5 to give Example 113 as a clear, colorlessfilm (35 mg, 51%).

¹H NMR (400 MHz, CDCl₃) δ: 6.81-6.73 (m, 3H), 3.85-3.59 (c, 11H),2.99-2.98 (d, 1H), 2.03-1.15 (c, 17H), 0.73 (s, 3H), 0.64-0.60 (m, 2H),0.35-0.32 (m, 2H).

LRMS (Electrospray, positive): Da/e 446.5 (m+1).

EXAMPLE 114

R¹=CH₂C₃H₅; R³=(R)—COCH(C₄H₉)NHCO₂CH₂Ph

N-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-butyl-2-oxoethyl)(phenylmethoxy)-carboxamide

Intermediate 67 (41 mg, 0.013 mmol) was coupled by the Hunig's baseprocedure of Intermediate 74 with Z-D-Nle-ONp (57 mg, 0.15 mmol, 1.1 eq)to give Example 114 as a clear, colorless oil (29.9 mg, 40%).

LRMS (Electrospray, positive): Da/e 553.6 (m+1).

EXAMPLE 115

R¹=CH₂C₃H₅; R³=(R)—COCH(C₄H₉)NH₂

(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-aminohexan-1-one

Example 114 (29.9 mg, 0.054 mmol) was subjected to the debenzylationprocedure of Intermediate 31 to give Example 115 as a white powder (18.8mg, 83%).

¹H NMR (400 MHz, CDCl₃) δ: 6.83-6.62 (m, 3H), 4.17-4.08 (m, 2H),3.85-3.61 (c, 9H), 3.32-3.29 (t, 1H), 3.13-3.11 (d, 1H), 2.04-1.78 (m,3H), 1.52-1.21 (c, 10H), 0.92-0.88 (t, 3H), 0.62-0.58 (m, 5H), 0.34-0.30(m, 2H). LRMS (Electrospray, positive): Da/e 419.4 (m+1).

EXAMPLE 115

R¹=CH₂C₃H₅; R³=(R)—COCH(i-Pr)NHCO₂CH₂Ph

N-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-(methylethyl)-2-oxoethyl)(phenyl-methoxy)carboxamide

Intermediate 67 (41 mg, 0.13 mmol) was coupled by the Hunig's baseprocedure of Intermediate 74 with Z-D-Val-OSu (52.2 mg, 0.15 mmol, 1.1eq) to yield Example 116 as a clear, colorless oil (64.8 mg, 89%).

¹H NMR (400 MHz, CDCl₃) δ: 7.35-7.32 (m, 5H), 6.81-0.69 (m, 3H),5.65-5.61 (t, 3H), 5.28-5.01 (m, 2H), 4.34-2.78 (m, 10H), 2.08-1.98 (m,1H), 1.31-0.91 (c, 8H), 0.71-0.68 (d, 3H), 0.64-0.59 (m, 2H), 0.38-0.31(m, 2H).

EXAMPLE 117

R¹=CH₂C₃H₅; R³=(R)—COCH(i-Pr)NH₂

(4R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-amino-3-methylbutan-1-one

Example 116 (64.8 mg, 0.120mmol) was subjected to the debenzylationprocedure of Intermediate 31 to give Example 117 as a clear solid (38.9mg, 80%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.77-6.59 (m, 3H), 4.41(s, 1H), 4.23-4.12 (m, 2H), 3.85-3.60 (c, 9H), 3.24 (s, 1H), 3.15-3.13(d, 1H), 2.40 (br s, 1H), 1.29-1.14 (m, 11H), 0.62-0.58 (m, 5H),0.33-0.29 (m, 2H). LRMS (Electrospray, positive): Da/e 405.5 (m+1).

EXAMPLE 118

R¹=H; R³=COCH₂SAc

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-acetylthioethan-1-one

Intermediate 70 (173 mg, 0.694 mmol) was dissolved in dioxane (2mL), and1 M K₂CO₃ (1 mL) was added dropwise. Acetoxymercaptoacetic acid chloride(100 μL, 13.9 M in dioxane, 2 eq) was added, and the solution wasvigorously stirred for 1 hour. The solution was diluted with EtOAc (30mL) and the organic layers were washed with 1M K₂CO₃ (20 mL), then brine(20 mL). The organic layer was dried over Na₂SO₄, and concentrated invacuo. The resulting oil was chromatographed by silica column (1:1EtOAc:hexanes), yielding a clear, colorless oil (34 mg, 13%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.85-6.82 (m, 3H),3.92-2.98 (c, 12H), 2.39 (s, 3H), 1.15-1.11 (t, 3H), 0.75-0.73 (d, 3H).

EXAMPLE 119

R¹=CH₂C₃H₅; R³=COCH₂SAc

1-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropyl-methoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-acetylthioethan-1-one

To a flask containing anhydrous K₂CO₃ (52 mg, 0.37 mmol, 4.0 eq) under anitrogen atmosphere was added a solution of Example 118 (34 mg, 0.093mmol, 1 eq) in anhydrous DMF (1 mL). Cyclopropylmethyl bromide (40 μL,0.37 mmol, 4.0 eq) was added via syringe to the mixture. The slurry wasstirred at 65° C. overnight. The reaction was cooled to roomtemperature, then diluted with water (50 mL). The aqueous solution wasextracted with EtOAc (3×30 mL), and the combined organic layers werewashed with brine (50 mL), then dried over Na₂SO₄, filtered, andconcentrated in vacuo. The resulting oil was purified by precarative TLCplate (100% EtOAc), yielding a clear, colorless oil (13.9 mg, 36%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.10-6.75 (m, 3H),3.91-3.32 (c, 11H), 2.64-2.61 (m, 2H), 2.33-2.30 (d, 3H), 1.82-1.50 (brs, 2H), 1.38-1.04 (m, 2H), 0.75 (s, 3H), 0.56-0.55 (m, 2H), 3.27-0.23(m, 2H).

EXAMPLE 120

R¹=CH₂C₃H₅; R³=COCH₂SH

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-sulfanylethan-1-one

Example 119 (13.9 mg, 0.0329 mmol) was subjected to the LiOH hydrolysisprocedure of Intermediate 5 to give a clear, colorless oil (7.2 mg,58%).

¹H NMR (CD3OH, 400 MHz, mixture of rotomers) δ: 6.86-6.75 (m, 3H),3.83-3.11 (c, 13H), 2.60-2.56 (d, 2H), 1.39-0.85 (m, 4H), 0.76-0.74 (m,3H), 0.58-0.56 (m, 2H), 0.35-0.24 (m, 3H). LRMS (Electrospray,positive): Da/e 380.5 (m+1).

EXAMPLE 121

R¹=CH₂C₃H₅; R³=COCH₂NHCO₂CH₂Ph

N-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoethyl)(phenylmethoxy)carboxamide

Intermediate 67 was acylated by the Hunig's base procedure ofIntermediate 74 with N-CBZ-glycine p-nitrophenyl ester to give Example121.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.42-7.28 (m, 5H),6.83-6.75 (m, 3H), 5.87-5.80 (m, 1H), 5.13 (s, 2H), 4.08-3.15 (c, 13H),1.39-1.24 (m, 1H), 1.14 (t, 3H), 0.73 (d, 3H), 0.66-0.59 (m, 2H),0.39-0.31 (m, 2H)

EXAMPLE 122

R¹=CH₂C₃H₅; R³=COCH₂NH₂

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-aminoethan-1-one

Example 121 was subjected to the debenzylation procedure of Intermediate31 to give Example 122.

¹H NMR (Methanol-d₄, 400 MHz, mixture of rotomers) δ: 6.94-6.84 (m, 3H),4.01-3.27 (c, 13H), 1.29-1.18 (m, 3H), 0.79-0.73 (m, 3H), 0.62-0.55 (m,2H), 0.35-0.29 (m, 2H). LRMS (Electrospray, positive): Da/e 363.2 (m+1).

EXAMPLE 123

R¹=CH₂C₃H₅; R³=COCH₂NHSO₂CH₃

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-[(methylsulfonyl)amino]ethan-1-one

Acylation of Example 122 by the Hunig's base coupling procedure ofIntermediate 74 using methane-sulfonyl chloride afforded Example 123.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.86-6.75 (m, 3H),5.48-5.42 (m, 1H), 4.00-3.57 (c, 11H), 3.46 and 3.15 (d and d, 1H), 3.00(s, 3H), 1.67 (dd, 1H), 1.36-1.24 (m, 1H), 1.16 (t, 3H), 0.76 (d, 3H),0.66-0.60 (m, 2H), 0.39-0.32 (m, 2H). LRMS (Electrospray, positive):Da/e 441.3 (m+1).

EXAMPLE 124

R¹=CH₂C₃H₅; R³=COCH₂NHSO₂CF₃

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-{((trifluoromethyl)sulfonyllamino}ethan-1-one

Sulfonation of Example 122 by the Hunig's base coupling procedure ofIntermediate 74 using trifluoromethanesulfonyl chloride afforded Example124.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.85-6.77 (m, 3H),4.11-3.10 (c, 13H), 1.15 (t, 3H), 0.76 (d, 3H), 0.66-0.60 (m, 2H),0.40-0.32 (m, 2H). LRMS (Electrospray, positive): Da/e 495.3 (m+1).

EXAMPLE 125

R¹=CH₂C₃H₅; R³=COCH₂NMe₂

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(dimethylamino)ethan-1-one

Solid Phase EDCI Coupling Reaction

A reaction vial equipped with a stir vane was charged with EDC resin(164 mg, 0.082 mmol, 0.5 mmol/g), NMP (2 mL), and N,N-dimethylglycine(20 mg, 0.143 mmol). The resulting mixture was allowed to stir at roomtemperature for one hour. Intermediate 67 then was added, and themixture was stirred at room temperature for 20 hours, then filtered. Theresin was washed with several portions of NMP. All the washings andfiltrate were combined and subjected to reduced pressure to remove thesolvent. Biotage purification on the residue (12S cartridge, 5%MeOH/CH₂Cl₂/0.1% NH₄OH) afforded 8 mg (25%) of a clear film.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.87-6.72 (m, 3H),4.07-2.97 (c, 13H), 2.35 (d. 6H), 1.35-1.25 (m, 1H), 1.17 (t, 3H), 0.74and 0.64 (s and s, 3H), 0.66-0.50 (m, 2H), 0.37-0.32 (m, 2H). LRMS(Electrospray, positive): Da/e 391.5 (m+1).

EXAMPLE 126

R¹=CH₂C₃H₅; R³=(S)—COCH(Me)NHCO₂CH₂Ph

N-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-methyl-2-oxoethyl)(phenylmethoxy)-carboxamide

Acylation of Intermediate 67 by the solid phase EDCI procedure ofExample 125 with Z-Ala-ONp afforded Example 126.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.38-7.26 (m, 5H),6.84-6.74 (m, 3H), 5.86 (dd 1H), 5.14-5.08 (m, 2H), 4.56 (quintet, 1H),3.87-3.32 (c, 11H), 1.43-1.34 (dd, 3H), 1.33-1.24 (m, 1H), 1.13 (d, 3H),0.74 (s, 3H), 0.66-0.59 (m, 2H), 0.37-0.32 (m, 2H). LRMS (Electrospray,positive): Da/e 511.7 (m+1).

EXAMPLE 127

R¹-CH₂C₃H₅; R³=(S)—COCH(CH₃) NH₂

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-²-aminopropan-1-one

Example 126 was subjected to the procedure of Intermediate 31 to affordExample 127.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 8.44-8.16 (br s, 2H),6.82-6.56 (m, 3H), 4.53-3.02 (c, 12H), 1.43-1.34 (dd, 3H), 1.33-1.24 (m,1H), 1.13 (d, 3H), 0.74 (s, 3H), 0.66-0.59 (m, 2H), 0.37-0.32 (m, 2H).LRMS (Electrospray, positive): Da/e 377.3 (m+1).

EXAMPLE 128

R¹=CH₂C₃H₅; R³=(R)—COCH(CH₃) NHCO₂CH₂Ph

N-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-methyl-2-oxoethyl)(phenylmethoxy)-carboxamide

Prepared from Intermediate 67 via the acylation procedure of Example 7with Z-D-Ala-OSu.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.40-7.28 (m, 5H),6.85-6.74 (m, 3H), 5.80 (t 1H), 5.10 (d, 2H), 4.57-4.47 (m, 1H),3.99-3.12 (c, 11H), 1.40-1.24 (m, 4H), 1.14 (d, 3H), 0.73 (s, 3H),0.66-0.59 (m, 2H), 0.38-0.31 (m, 2H). LRMS (Electrospray, positive):Da/e 511.6 (m+1).

EXAMPLE 129

R¹=CH₂C₃H₅; R³=(R)—OCH(C₃)N₂

(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-aminopropan-1-one

Prepared from Example 128 via the debenzylation procedure ofIntermediate 31.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 8.60-8.27 (br m, 3H),6.87-6.58 (m, 3H), 4.75-3.10 (c, 12H), 1.74-1.59 (m, 3H), 1.33-1.05 (m,4H), 0.66-0.55 (m, 5H), 0.35-0.27 (m, 2H). LRMS (Electrospray,positive): Da/e 377.2 (m+1).

EXAMPLE 130

R¹=CH₂C₃H₅; R³=(S)—COCH(i-Pr)NHCO₂CH₂Ph

N-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-(methylethyl)-2-oxoethyl)(phenyl-methoxy)carboxamide

Prepared from Intermediate 67 via the acylation procedure of Example 7using Z-Val-ONp.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.42-7.27 (m, 5H),6.84-6.75 (m, 3H), 5.63 (dd 1H), 5.15-5.02 (m, 2H), 4.40-4.4.07 (dm,1H), 3.87-3.33 (c, 12H), 2.08-1.95 (m, 1H), 1.34-1.25 (m, 1H), 1.14 (t,3H), 1.04-0.90 (m, 6H), 0.73 (s, 3H), 0.66-0.59 (m, 2H), 0.38-0.31 (m,2H). LRMS (Electrospray, positive): Da/e 539.5 (m+1).

EXAMPLE 131

R¹=CH₂C₃H₅; R³=(S)—COCH(i-Pr)NH₂

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-amino-3-methylbutan-1-one

Prepared from Example 130 via the debenzylation method of Intermediate31.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 8.37 (br s, 3H),6.82-6.63 (m, 3H), 4.24-3.53 (c, 11H), 3.19 (d, 1H), 2.45-2.32 (m, 2H),1.34-1.04 (m, 10H) 0.64 (s, 3H), 0.63-0.56 (m, 2H), 0.36-0.29 (m, 2H).LRMS (Electrospray, positive): Da/e 405.4 (m+1).

EXAMPLE 132

R¹=CH₂C3H₅; R³=(S)—COCH(CH₂CH(CH₃)CH₃)NHCO₂CH₂Ph

N-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl)-3-methylpyrrolidinyl}(1S)-1-(2-methylpropyl)-2-oxoethyl)(phenylmethoxy)carboxamide

Prepared from Intermediate 67 via the Hunig's base acylation procedureof Intermediate 74 using Z-Leu-ONp.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.43-7.26 (m, 5H),6.84-6.75 (m, 3H), 5.61 (dd 1H), 5.16-5.04 (m, 2H), 4.63-4.55 (m, 1H),3.90-3.34 (c, 12H), 1.80-1.68 (m, 1H), 1.64-1.40 (m, 2H), 1.36-1.24 (m,1H), 1.14 (d, 3H), 1.05-0.92 (m, 6H) 0.74 (d, 3H), 0.65-0.59 (m, 2H),0.37-0.32 (m, 2H). LRMS (Electrospray, positive): Da/e 553.7 (m+1).

EXAMPLE 133

R¹=CH₂C₃H₅; R³=(S)—COCH(CH₂CH(CH₃)CH₃)NH₂

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-amino-4-methylpentan-1-one

Prepared from Example 132 via the debenzylation method of Intermediate31.

¹H NMR (Methanol-d₄, 400 MHz, mixture of rotomers) δ: 6.96-6.86 (m, 3H),4.33-4.28 (m, 1H), 4.03-3.28 (c, 11H), 1.87-1.65 (m, 3H), 1.29-1.18 (m,1H), 1.14-0.96 (m, 9H), 0.76 (d, 3H), 0.61-0.55 (m, 2H), 0.36-0.29 (m,2H). LRMS (Electrospray, positive): Da/e 419.5 (m+1).

EXAMPLE 134

R¹=CH₂C₃H₅; R³=(R)—COCH(CH₂CH(CH₃)CH₃)NHCO₂CH₂Ph

N-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-(2-methylpropyl)-2-oxoethyl)(phenylmethoxy)carboxamide

Prepared from Intermediate 67 via the Hunig's base acylation method ofIntermediate 74 using Z-D-Leu-ONp.

¹H NMR (400 MHz, CDCl₃ mixture of rotomers) δ: 7.40-7.28 (m, 5H),6.85-6.70 (m, 3H), 5.57 (dd 1H), 5.14-5.04 (m, 2H), 4.58-4.49 (m, 1H),4.11-3.19 (c, 11H), 1.78-1.66 (m, 1H), 1.60-1.22 (m, 3H), 1.15 (dd, 3H),1.03-0.85 (m, 6H) 0.72 (d, 3H), 0.65-0.57 (m, 2H), 0.38-0.30 (m, 2H).LRMS (Electrospray, positive): Da/e 553.7 (m+1).

EXAMPLE 135

R¹=CH₂C₃H₅; R³=(R)—COCH(CH₂CH(CH₃)CH₃)NH₂

(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-amino-4-methylpentan-1-one

Prepared from Example 134 via the debenzylation method of Intermediate31.

¹H NMR (Methanol-d₄, 400 MHz, mixture of rotomers) δ: 6.97-6.91 (m, 2H),6.88-6.83 (m, 1H), 4.29-3.25 (c, 11H), 1.85-1.59 (m, 3H), 1.30-1.19 (m,1H), 1.10 (dd, 3H), 1.06-0.93 (m, 6H), 0.77 (dd, 3H), 0.62-0.55 (m, 2H),0.36-0.29 (m, 2H). LRMS (Electrospray, positive): Da/e 419.5 (m+1).

EXAMPLE 136

R¹=CH₂C₃H₅, R³=COCH(C₄H₉)NHCO₂CH₂Ph

N-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-butyl-2-oxoethyl)(phenylmethoxy)carboxamide

Prepared from Intermediate 67 via the acylation method of Example 7using Z-NLeu-ONp.

¹H NMR (400 MHz, CDCl₃ mixture of rotomers) δ: 7.40-7.25 (m, 5H),6.85-6.75 (m, 3H), 5.69 (dd 1H), 5.14-5.05 (m, 2H), 4.56-4.50 (m, 1H),3.87-3.34 (c, 11H), 1.80-1.54 (m, 2H), 1.43-1.24 (m, 5H), 1.14 (m, 3H),0.96-0.85 (m, 3H) 0.74 (s, 3H), 0.65-0.61 (m, 2H), 0.37-0.32 (m, 2H).LRMS (Electrospray, positive): Da/e 553.8 (m+1).

EXAMPLE 137

R¹=CH₂C₃H₅; R³=COCH(C₄H₉) NH₂

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-aminohexan-1-one

Prepared from Example 136 via the debenzylation method of Intermediate31.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.93-6.85 (m, 3H),4.33-4.25 (m, 1H), 4.02-3.47 (c, 11H), 1.96-1.79 (m, 2H), 1.51-1.35 (m,4H), 1.30-1.19 (m, 1H), 1.11 (dd, 3H), 1.03-0.93 (m, 3H) 0.77 (d, 3H),0.62-0.56 (m, 2H), 0.35-0.30 (m, 2H). LRMS (Electrospray, positive):Da/e 419.5 (m+1).

EXAMPLE 138

R¹=CH₂C₃H₅; R³=(R)—COCH(C₆H₁₁)NH₂CO₂CH₂Ph

N-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-(1R)-cyclohexyl-2-oxoethyl)(phenylmethoxy)carboxamide

EDCI/HOBT Coupling Procedure

A reaction vial equipped with a stir vane was charged withN-carboxybenzyl-D-cyclohexylglycine (23.8 mg, 0.0819 mmol), dry CH₂Cl₂(350 ul), EDCI (15.7 mg, 0.0819 mmol), and hydroxybenzotriazole (HOBT)(12.5 mg, 0.0819 mmol). This mixture was allowed to stir at roomtemperature for 1 hour, and Intermediate 67 (25 mg, 0.0819 mmol) wasadded in one portion. After stirring at room temperature for 48 hours,the reaction mixture was diluted with CH₂Cl₂ 5 mL), washed with 1N HCl(2×20 mL), saturated NaHCO₃ solution (1×20 ml), dried (Na₂SO₄), andconcentrated to 27 mg (57%) of a white foam.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.39-7.29 5m, 5H),6.86-6.78 (m, 2H), 6.75-6.68 (m, 1H), 5.54 (dd, 1H), 4.37-3.25 (c, 12H),1.81-1.56 (m, 5H), 1.36-0.95 (m, 10H), 0.71 (d, 3H), 0.66-0.59 (m, 2H),0.39-0.31 (m, 2H). LRMS (Electrospray, positive): Da/e 580.2 (m+1).

EXAMPLE 139

R¹=CH₂C₃H₅; R³=(S)—COCH(C₆H₁₁)NH₂

(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-amino-2-cyclohexylethan-1-one

Prepared from Example 138 via the debenzylation procedure ofIntermediate 31.

¹H NMR (Methanol-d₄, 400 MHz, mixture of rotomers) δ: 6.95-6.78 (m, 3H),4.10-3.20 (c, 12H), 1.96-1.62 (m, 5H), 1.39-1.02 (m, 10H), 0.75 (d, 3H),0.62-0.51 (m, 2H), 0.35-0.23 (m, 2H). LRMS (Electrospray, positive):Da/e 445.5 (m+1).

EXAMPLE 140

R¹=CH₂C₃H₅; R³=(S)—COCH(t-Bu)NHCO₂CH₂Ph

N-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-(1S)-cyclohexyl-2-oxoethyl)(phenylmethoxy)carboxamide

Prepared from Intermediate 67 via the EDCI/HOBT coupling procedure ofExample 138 using N-carboxybenzyl-L-t-butylglycine.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.39-7.29 (m, 5H),6.64-6.76 (m, 3H), 5.59-5.53 (m, 1H), 5.14-5.02 (m, 2H), 4.34 (dd, 1H),3.87-3.33 (c, 10H), 1.34-1.24 (m, 1H), 1.14 (dd, 3H), 0.74 (d, 3H),0.66-0.59 (m, 2H), 0.39-0.31 (m, 2H). LRMS (Electrospray, positive):Da/e 554.2 (m+1).

EXAMPLE 1411-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-amino-3,3-dimethylbutan-1-one

Prepared from Example 140 via the debenzylation procedure ofIntermediate 31.

¹H NMR (Methanol-d₄, 400 MHz, mixture of rotomers) δ: 6.98-6.86 (m, 3H),4.16-3.33 (c, 12H), 1.29-1.20 (m, 1H), 1.15-0.97 (m, 12H), 0.75 (d, 3H),0.62-0.56 (m, 2H), 0.36-0.30 (m, 2H). LRMS (Electrospray, positive):Da/e 419.5 (m+1).

EXAMPLE 1421-{(3R)-3-((1R)-1-Hydroxyethyl)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(phenylmethoxy)ethan-1-one

Intermediate 73 (775 mg, 2.53 mmol) was coupled with benzyloxyacetylchloride (497 μL, 3.16 mmol) by the Hunig's base procedure ofIntermediate 74 to give Example 134 as a brown foam (978 mg, 85%).

¹H-NMR (400 MHz, CDCl₃) δ: 7.41-7.30 (m, 5H), 6.90 (m, 2H), 6.81 (d,1H), 4.64 (dd, 2H), 4.15 (dd, 2H), 3.95 (dd, 1H), 3.80 (s, 3H), 3.62(dd, 1H), 3.57 (m, 2H), 3.44 (d, 1H), 3.21 (d, 1H), 1.33 (s, 9H), 1.16and 1.11 (two doublets, 3H, rotomers), 0.73 (d, 3H, rotomers).

EXAMPLE 143

R¹=H; R³=COCH₂OCH₂Ph

1-[(3R)-3-((1R)-1-Hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(phenylmethoxy)-ethan-1-one

To a stirred solution of Example 142 (750 mg, 1.65 mmol) in CH₂Cl₂ (6.6mL) at 0° C. under a drying tube was added trifluoroacetic acid (763 μL,9.9 mmol). Cooling was removed from the reaction, and it was allowed towarm to room temperature, then stirred for 3.5 hours. The reaction wasconcentrated by rotary evaporation to remove excess trifluoroaceticacid, then was diluted with CH₂Cl₂ (30 mL), and washed with 10% Na₂CO₃(2×30 mL). The organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo to provide Example 143. Flash chromatography inEtOAc gave, after pooling and concentration an vacuo of productcontaining fractions, Example 143 as a white foam (650 mg, 98%).

¹H-NMR (400 MHz, CDCl₃, δ: 7.42 (m, 5H), 6.83-6.70 (m, 3H), 4.64 (s, 2H)4.16 (s, 2H), 3.93 (dd, 1H), 3.85 (s, 3H), 3.78 (d, 1H), 3.74 (dd, 2H),3.67-3.52 (m, 4H), 3.44 (d, 1H), 3.20 (d, 1H), 1.16 and 1.10 (doubles,3H, rotomers), 0.73 (s, 3H).

EXAMPLE 144

R¹=CH₂C(CH₃)(CH₂CH₂); R³=COCH₂OCH₂Ph

2-Benzyloxy-1-(3-((1R)-1-hydroxyethyl)-(3S,4S)-4-[4-methoxy-3-(1-methylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl)ethanone

Solid Phase Mitsunobu Procedure

To a stirred solution of Example 143 (40 mg, 0.1 mmol) in THF (1.5 mL)at room temperature in a capped conical reaction vial was addedPS-triphenylphosohine (1.65 mmol/g, 182 mg, 0.3 mmol). After allowingthe suspension to slowly stir for 5 minutes to permit gel swelling,1-methylcyclopropaneMethanol (29 μL, 0.3 mmol) was added, and thereaction cooled to 0° C. The suspension then was treated with DIAC (59μL, 0.3 mmol), and the reaction warmed to 65° C.

After stirring slowly overnight, the reaction was cooled to roomtemperature and filtered through a polystyrene frit with THF (30 M). Thefiltrate was concentrated in vacuo and flash chromatographed on a 15mm×6″ column with 1/1/0.1 EtOAc/hexane/Methanol and product containingfractions pooled and concentrated in vacuo to provide Example 144 as ayellow oil (40 mg, 86%). ¹H-NMR (400 MHz, CDCl₃) δ: 7.42-7.25 (m, 5H),6.83-6.77 (m, 3H), 4.63 (s, 2H), 4.15 (dd, 2H), 3.96-3.20 (m, 6H,rotomers), 3.81 (s, 3H), 1.74 (m, 1H), 1.24 (s, 3H), 1.17 and 1.10(doublets, 3H, rotomers), 0.72 (d, 3H, rotomers), 0.53 (m, 2H), 0.41 (m,2H).

EXAMPLE 145

R¹=CH₂C(CH₃)(CH₂CH₂); R³=CCCH₂OH

1-((3R)-3-((1R)-1-Hydroxyethyl)-4-{4-methoxy-3-[(methylcyclopropyl)methoxy]phenyl}-3-methylpyrrolidinyl)-2-hydroxyethan-1-one

The crude product of Example 144 (40 mg, 0.086 mmol) was subjected tothe debenzylation procedure of

Intermediate 31 to give Example 145 as a clear oil (32.5 mg, 100%).

¹H-NMR (CDCl₃/CD₃OD, 400 MHz) δ: 6.87-6.79 (m, 3H), 3.97-3.18 (m, 7H,rotomers), 3.83 (s, 3H), 1.23 (s, 3H), 1.14 and 1.11 (doublets, 3H,rotomers), 0.77 (s, 3H), 0.56 (m, 2H), 0.42 (m, 2H). LRMS (Electrospray,positive): Da/e 378.2 (m+1).

EXAMPLE 146

R¹=CH₂CH₂C₃H₅; R³=COCH₂OCH₂Ph

2-Benzyloxy-1-[(3S,4S)-4-[3-(2-cyclopropylethoxy)-4-methoxyphenyl]-3-((1R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone

Example 143 was subjected to the procedure of Example 144 using2-cyclopropylethanol (26 mg, 0.3 mmol) to provide Example 146 (41 mg,88%). ¹H-NMR (400 MHz, CDCl₃) δ: 7.41-7.25 (m, 5H), 6.82-6.74 (m, 3H),4.63 (s, 2H), 4.15 (dd, 2H), 4.04 (dd, 2H), 3.98-3.20 (m, 5H, rotomers),3.81 (s, 3H), 1.82 and 1.79 (m, 1H, rotomers), 1.72 (dd, 2H), 1.40-1.20(m, 1H), 1.18 and 1.12 (d, 3H, rotomers), 0.82 (m, 1H), 0.74 (s, 3H),0.46 (m, 2H), 0.12 (m, 2H).

EXAMPLE 147

R¹=CH₂CH₂C₃H,; R³=COCH₂OH

1-{(3R)-3-((1R)-1-Hydroxyethyl)-4-[3-(2-cyclopropylethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one

Example 146 was subjected to the debenzylation procedure of Intermediate31 to provide Example 147 as a clear oil (27.4 mg, 82%).

¹H-NMR (CDCl₃/CD₃OD, 400 MHz) δ: 6.91-6.80 (m, 3H), 4.19 (m, 2H), 4.10(m, 2H), 3.97-3.15 (m, 5H, rotomers), 3.82 (s, 3H), 1.73 (dd, 2H), 1.25(m, 1H), 1.14 and 1.12 (doublets, 3H, rotomers), 0.85 (m, 1H), 0.78 (s,3H), 0.46 (m, 2H), 0.14 (m, 2H). LRMS (Electrospray, positive): Da/e378.5 (m+1).

EXAMPLE 148

R¹=CH₂CH₂C₅H₉; R³=COCH₂OH

1-{(3R)-3-((1R)-1-Hydroxyethyl)-4-[3-(2-cyclopentylethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one

Prepared using the procedure of Example 144 using Example 143 and2-cyclopentylethanol (34 mgq, 0.3 mmol) to provide Example 148 (41 mg,100%) ¹H-NMR (400 MHz, CDCl₃) δ: 7.41-7.25 (m, 5H), 6,82-6.74 (m, 3H),4.63 (s, 2H), 4.15 (dd, 2H), 3.99 (dd, 2H), 3.98-3.20 (m, 5H, rotomers),3.81 (s, 3H), 2.00-1.20 (m, 11H), 1.18 and 1.12 (d, 3H, rotomers), 0.7 4(s, 3H).

EXAMPLE 1491-[(3S,4S)-4-[3-(2-cyclopentylethoxy)-4-methoxyphenyl]-3-((1R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone

Example 148 was subjected to the debenzylation Procedure of Intermediate31 to afford the product as as a clear oil (34.7 mg, 86%).

¹H-NMR (CDCl₃/CD₃OD, 400 MHz) δ: 6.87-6.80 (m, 3H), 4.18 (m, 2H), 4.03(m, 2H), 3.99-3.11 (m, 5H, rotomers), 3.84 (s, 3H), 2.01-1.15 (m, 11H),1.14 and 1.11 (doublets, 3H, rotomers), 0.77 (s, 3H). LRMS(Electrospray, positive): Da/e 406.4 (m+1).

EXAMPLE 1502-Benzyloxy-1-[4-(S)-[3-(bicyclo[4.1.0]hept-7-yl-methoxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone

Prepared from 143 by the Mitsunobu reaction of Example 144 usingbicyclo[4.1.0]hept-7-yl-Methanol to afford an 80:20 mixture of cis andtrans isomers (34% yield).

¹H NMR (CDCl₃, 400 MHz) δ: 7.42-7.23 (m, 5H), 6.85-5.72 (m, 3H),5.06-4.89 (m, 1H), 4.67 (s, 2H), 4.15 (s, 2H), 4.07-3.56 (m, 9H),2.09-1.56 (m, 8H), 1.36-0.87 (m, 8H), 0.73 (m, 3H). LRMS (Electrospray,positive): Da/e 508.6 (m+1).

EXAMPLE 1511-[4-(S)-[3-(Bicyclo[4.1.0]hept-7-ylmethoxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone

Example 150 (15 mg, 30 mmol) was dissolved in 95% ethanol (1 mL) and thesolution was treated with Pearlman's catalyst (20% Pd(OH)₂ on carbon, 15mg) The reaction mixture was hydrogenolyzed at 1 atmosphere (or at 50psi) of hydrogen for 16 hours. The reaction mixture was filtered toremove the catalyst, then the solvent was removed with a stream ofnitrogen. The product was purified by chromatography on silica gel ifnecessary using EtOAc/hexanes/Methanol (1:1:0.2). (76% yield). ¹H NMR(CDCl₃, 400 MHz) δ: 6.73-6.66(m, 3H), 4.04-3.99 (m, 2H), 3.94-3.87 (m,4H), 3.83-3.20 (m, 7H), 3.15-2.73 (m, 1H), 1.78-1.47 (m, 5H), 1.14-0.69(10H), 0.63-0.60 (3H). LRMS (Electrospray, positive): Da/e 418.3 (m+1).

EXAMPLE 1522-Benzyloxy-1-[4-(S)-[3-(bicyclo[3.1.0]hex-6-ylmethoxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone

Prepared from 143 by the Mitsunobu method of Example 144 usingbicyclo[3.1.0]hex-6-yl-Methanol. The product was an inseparable mixtureof isomers at the alcohol side chain (32% yield). ¹H NMR (CDCl₃, 400MHz) δ: 7.45-7.29 (m, 5H), 6.84-5.72 (m, 3H), 5.02-4.94 (m, 1H), 4.66(s, 2H), 4.16 (s, 2H), 4.08-3.44 (m, 8H), 1.96-1.51 (m, 4H), 1.26 (d,6H), 1.18-1.08 (dd, 5H), 0.72 (m, 3H). LRMS (Electrospray, positive):Da/e 494.4 (m+1).

EXAMPLE 1531-[4-(S)-[3-(Bicyclo[3.1.0]hex-6-ylmethoxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone

Prepared from Example 152 by the dibenzylation method of Example 151(90% yield).

¹H NMR (CD₃OD, 400 MHz) δ: 6.87-6.79 (m, 3H), 4.97-4.90 (m, 1H),4.19-4.14 (m, 2H),3.99-3.36 (m, 7H), 3.30-2.89 (m, 1H), 1.92-1.52 (m,4H), 1.28 (d, 6H), 1.16-1.06 (m, 6H), 0.77 (m, 3H). LRMS (Electrospray,positive): Da/e 404.3 (m+1).

EXAMPLE 1542-Benzyloxy-1-[4-(S)-[3-(4-tert-butylcyclohexyloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone

Prepared by the Mitsunobu method of Example 144 using Example 143 and4-tert-butyl-cyclohexanol (17% yield). ¹H NMR (CDCl₃, 400 MHz) δ:7.43-7.28 (m, 5H), 6.85-6.73 (m, 3H), 6.37 (brd s, 1H), 5.02-4.93 (m,2H), 4.67 (s, 2H), 4.13 (m, 2H), 3.89-3.43 (m, 7H), 2.19-1.36 (m, 8H),1.26 (d, 9H), 1.18-1.08 (dd, 1H), 0.92-0.81 (m, 6H). LRMS (Electrospray,positive): Da/e 538.8 (m+1).

EXAMPLE 1551-[4-(S)-[3-(4-tert-Butylcyclohexyloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone

Prepared from Example 154 by the dibenzylation procedure of Example 151(89% yield).

¹H NMR (CD₃OD, 400 MHz) δ: 6.82-6.74 (m, 3H), 4.91-4.85 (m, 3H),3.82-3.78 (m, 4H), 3.76-3.30 (m, 4H), 2.14-1.34 (m, 2H), 1.22-1.18 (m,10H), 1.08-0.99 (m, 3H), 0.86-0.78 (m, 9H), 0.79-0.75 (m, 3H). LRMS(Electrospray, positive): Da/e 448.8 (m+1).

EXAMPLE 1562-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(4-methylcyclohexyloxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

Prepared from Example 143 by the Mitsunobu procedure using4-methylcyclohexanol (mixture of isomers) (10% yield).

¹H NMR (CDCl₃, 400 MHz) δ: 7.42-7.28 (m, 5H), 6.83-6.74 (m, 3H), 4.67(s, 2H), 4.40-4.36 (m, 1H), 4.15-4.12 (m, 2H), 3.97-3.44 (m, 8H),1.98-1.91 (m, 2H), 1.60-0.85 (m, 15H), 0.74-0.71 (d, 3H). LRMS(Electrospray, positive): Da/e 496.7 (m+1).

EXAMPLE 1572-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(4-methylcyclohexyloxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

Prepared from Example 156 by the debenzylation procedure of Example 151(quantitative yield).

¹H NMR (CD₃OD, 400 MHz) δ: 6.87-6.79 (m, 3H), 4.18-4.11 (m, 2H),3.98-3.70 (m, 1H), 3.69-3.36 (m, 10H), 3.09-2.89 (m, 1H), 1.99-1.92 (m,1H), 1.61-1.43 (m, 6H), 1.28-1.25 (m, 2H), 1.14-1.10 (m, 3H), 0.97-0.86(m, 3H), 0.78-0.76 (m, 3H). LRMS (Electrospray, positive): Da/e 406.6(m+1).

EXAMPLE 1582-Benzyloxy-1-[4-(S)-[3-(decahydronaphthalen-2-yloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone

Prepared from Example 143 by the Mitsunobu procedure usingdecahydronaphthalen-2-ol (mixture of isomers) (10% yield).

¹H NMR (CDCl₃, 400 MHz) δ: 7.42-7.29 (m, 5H), 6.85-6.74 (m, 3H),5.03-4.95 (m, 1H), 4.68 (s, 2H), 3.98-3.45 (m, 7H), 1.90-1.10 (m, 22 H),0.75-0.72 (m, 3H) LRMS (Electrospray, positive): Da/e 536.7 (m+1).

EXAMPLE 1591-[4-(S)-[3-(Decahydronaphthalen-2-yloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone

Prepared from Example 158 by the debenzylation procedure of Example 151(quantitative yield).

¹H NMR (CDCl₃, 400 MHz) δ: 6.85-6.79 (m, 3H), 5.02-4.94 (m, 1H),4.23-4.12 (m., 2H), 4.03-3.48 (m, 10H), 3.08-2.89 (m, 1H), 1.89-1.80 (m,2H), 1.78-1.13 (m, 17H), 0.77-0.75 (m, 3H). LRMS (Electrospray,positive): Da/e 446.1 (m+1).

EXAMPLE 1602-Benzyloxy-1-[4-(S)-[3-(bicyclohexyl-4-yloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone

Prepared from Example 143 by the Mitsunobu procedure usingbicyclohexyl-4-ol (mixture of isomers) (12% yield).

¹H NMR (CDCl₃, 400 MHz) δ: 7.42-7.29 (m, 5H), 6.84-6.74 (m, 3H),5.03-4.95 (m, 1H), 4.68 (s, 2H), 4.17-4.11 (m, 2H), 3.98-3.45 (m, 7H),1.90-1.10 (m, 26H), 0.75-0.72 (m, 3H). LRMS (Electrospray, positive):Da/e 564.8 (m+1).

EXAMPLE 1611-[4-(S)-[3-(Bicyclohexyl-4-yloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone

Prepared from Example 160 by the debenzylation procedure of Example 151(quantitative yield).

¹H NMR (CDCl₃, 400 MHz) δ: 6.85-6.79 (m, 3H), 5.02-4.93 (m, 1H),4.20-4.15 (m, 2H), 4.07-3.47 (m, 8H), 3.07-2.88 (m, 1H), 2.17-1.94 (m,2H), 1,82-0.82 (m, 23H), 0.77-0.74 (brd s, 3H). LRMS (Electrospray,positive): Da/e 474.6 (m+1).

EXAMPLE 1622-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(4-trifluoromethylcyclohexyloxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

Prepared from Example 143 by the Mitsunobu procedure using4-trifluoromethylcyclohexanol (mixture of isomers) (40% yield)

¹H NMR (CDCl₃, 400 MHz) δ: 7.46-7.24 (m, 5H), 6.88-6.77 (m, 3H),4.72-4.61 (brd s, 2H), 5.03-4.89 (brd m, 1H), 4.19-3.18 (m, 10H),2.26-0.80 (m, 14H), 0.75-0.58 (brd, 3H). LRMS (Electrospray, positive):Da/e 550.7 (m+1).

EXAMPLE 1632-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(4-trifluoromethylcyclohexyloxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

Prepared from Example 162 by the debenzylation procedure of Example 151(quantitative yield).

¹H NMR (CDCl₃, 400 MHz) δ: 6.85-6.83 (m, 3H), 5.03-4.90 (m, 1H),4.26-4.15 (m, 2H), 4.13-3.95 (m, 2H), 3.89-3.37 (m, 7H), 3.10-2.90 (m,1H), 2.26-2.18 (m, 2H), 2.08-2.01 (m, 3H), 1.55-0.86 (m, 7H), 0.75 (s,3H). LRMS (Electrospray, positive): Da/e 460.3 (m+1).

EXAMPLE 1642-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(3-methoxy-3-methylbutoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

Prepared from example 143 by the Mitsunobu procedure using3-methoxy-3-methylbutanol (78% yield).

¹H NMR (CDCl₃, 400 MHz) δ: 7.42-7.29 (m, 5H), 6.85-6.72 (m, 3H), 4.67(s, 2H), 4.17-4.13 (m, 3H), 3.97-3.45 (m, 9H), 3.23 (d, 4H), 2.07-2.01(m, 2H), 1.23 (s, 6H), 1.16-1.09 (dd, 4H), 0.72 (d, 3H). LRMS(Electrospray, positive): Da/e 500.6 (m+1).

EXAMPLE 1652-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(3-methoxy-3-methylbutoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

Prepared from Example 164 by the debenzylation method of Example 151(97% yield).

¹H NMR (CDCl₃, 400 MHz) δ: 6.83-6.72 (m, 3H), 4.19-4.11 (m, 4H),4.01-3.79 (m, 1H), 3.83 (s, 3H), 3.72-3.46 (m, 7H), 3.22 (s, 3H),2.05-1.99 (m, 2H), 1.22 (brd s, 7H), 1.16-1.11 (m, 3H), 0.73 (brd s,3H). LRMS (Electrospray, positive): Da/e 410.2 (m+1).

EXAMPLE 1662-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(1-phanylcyclopentylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

Prepared from Example 143 by the Mitsunobu procedure using(1-phenylcyclopentyl)Methanol (25% yield).

¹H NMR (CDCl₃, 400 MHz) δ: 7.46-7.13 (m, 10H), 6.78-6.37 (m, 3H),5.01-4.93 (m, 1H), 4.66 (s, 2H), 4.15-4.10 (m, 2H), 3.92-3.41 (m, 7H),2.24-2.15 (m, 1H), 2.04-1.97 (m, 2H), 1.84-1.70 (m, 4H), 1.26 (d, 6H),1.13-1.05 (dd, 3H), 0.87-0.85 (m, 1H), 0.65 (2H). LPMS (Plectrospray,positive) Da/e 558.5 (m+1).

EXAMPLE 1672-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(1-phenylcyclopentylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

Prepared from Example 166 by the debenzylation procedure of Example 151(26o yield).

¹H NMR (CDCl₃, 400 MHz) δ: 7.46-7.43 (m, 2H), 7.34-7.27 (m, 2H)7.23-7.18 (m, 1H), 6.81-6.71 (m, 3H), 6.53-6.48 (m, 1H), 4.15-4.09 (m,2H), 3.93-3.88 (m, 2H), 3.78-3.46 (m, 7H), 2.25-0.68 (m, 17H). LRMS(Electrospray, positive): Da/e 468.7 (m+1).

EXAMPLE 1682-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(1-phenylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

Prepared from Example 143 by the Mitsunobu procedure using(1-phenylcyclopropyl)Methanol (90% yield).

¹H NMR (CDCl₃, 400 MHz) δ: 7.46-7.16 (m, 10H), 6.79-6.72 (m, 2H),6.64-6.59 (m, 1H), 4.66 (s, 2H), 4.14-4.12 (m, 2H), 4.10-4.02 (m, 2H),3.91-3.42 (m, 9H), 1.28-1.25 (m, 1H), 1.14-1.06 (m, 3H), 1.04-0.95 (m,4H), 0.66 (s, 3H). LRMS (Electrospray, positive): Da/e 530.7 (m+1).

EXAMPLE 1692-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(1-phenylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

Prepared from Example 168 by the debenzylation procedure of Example 151(44% yield).

¹H NMR (CDCl₃, 400 MHz) δ: 7.47-7.21 (m, 5H), 6.84-6.60 (m, 3H),4.15-4.04 (m, 4H), 3.99-3.46 (m, 8H), 3.05-2.99 (m, 1H), 2.11-2.04 (m,1H), 1.74-1.59 (m, 2H), 1.29-0.96 (m, 4H), 0.88-0.68 (m, 4H). LRMS(Electrospray, positive): Da/e 440.1 (m+1).

EXAMPLE 170

R¹=CH₂C(CH₂CH₃)(CH₂OCH₂); R³=COCH₂OCH₂Ph

2-Benzyloxy-1-[(3S,4S)-4-3-(3-ethyloxetan-3-ylmethoxy)-4-methoxyphenyl]-3-((1R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone

Prepared from Example 143 according to the procedure in Example 144using 3-ethyl-3-oxetaneMethanol (34 mL, 0.3 mmol) to yield Example 150(44 mg, 88%).

¹H-NMR (400 MHz, CDCl₃) δ: 7.41-7.25 (m, 5H), 6.84-6.80 (m, 3H), 4.64(s, 2H), 4S.5 (dd, 2H), 4.49 (d, 2H), 4.17-4.11 (m, 3H), 3.99 (dd, 2H),3.98-3.20 (m, 5H, rotomers), 3.80 (s, 3H), 1.91 (dd, 2H), 1.80 (d, 1H),1.24 (dd, 1H), 1.17 and 1.13 (doublets, 3H, rotomers), 0.94 (t, 3H),0.73 (s, 3H).

EXAMPLE 171

R¹=CH₂C(CH₂CH₃)(CH₂OCH₂); R³=COCH₂OH

1-((3R)-3-((1R)-1-Hydroxyethyl)-4-{3-[(3-ethyloxetan-3-yl)methoxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)-2-hylroxyebhan-1-one

Example 170 was deprotected using the debenzylation of Intermediate 31to provide Example 171 as a clear oil (28.6 mg, 80%).

¹H-NMR (CDCl₃/CD₃OD, 400 MHz) δ: 6.91-6.83 (m, 3H), 4.64 (d, 1H), 4.19(m, 2H), 4.12 (m, 1H), 4.00-3.14 (m, 12H), 3.83 (s, 3H), 1.15 (m, 3H),0.96 (m, 3H), 0.78 (s, 3H). LRMS (Electrospray, positive): Da/e 408.5(m+1).

EXAMPLE 172

R¹=t-Bu; R³=COCH₂OAc

(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoethylAcetate

Prepared from Intermediate 73 via the Hunig's base coupling procedure ofIntermediate 74 using acetoxyacetyl chloride.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.94-6.81 (m, 3H),4.72-4.58 (m, 2H), 3.80 (m, 3H), 3.97-3.17 (m, 6H), 2.19 (s, 3H), 1.33(d, 9H), 1.15 (t, 3H), 0.76 (d, 3H).

EXAMPLE 173

R¹=H; R³=COCH₂OAc

2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoethylAcetate

Example 172 was deprotected by the TFA method of Example 143 to affordExample 173 as a tan foam (173 mg, 80%)

¹H MMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.86-6.70 (m, 3H), 5.64(br s, 1H), 4.72-4.62 (m, 2H), 3.88 (m, 3H), 3.95-3.18 (c, 6H), 2.20 (d,3H), 1.15 (t, 3H), 0.77 (d, 3H). LRMS (Electrospray, positive): Da/e352.2 (m+1).

EXAMPLE 174

R¹=4-Ph—Ph—CH₂CH₂; R³=C(═O)CH₂OCH₂Ph

2-Benzyloxy-1-[(3S,4S)-4-[3-(2-biphenyl-4-ylethoxy)-4-methoxyphenyl]-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone

Example 143 (60 mg, 0.15 mmol) was subjected to the Mitsunobu procedureof Example 144 using 4-hydroxyethylbiphenyl (90 mg, 0.45 mmol) and usedwithout further Purification or characterization (73 mg,

EXAMPLE 175

R¹=4-Ph—Ph—CH₂CH₂; R³=C(═O)CH₂OH

1-[(3S,4S)-4-[3-(2-Biphenyl-4-ylethoxy)-4-methoxyphenyl]-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone

Example 174 was subjected to the debenzylation procedure of Intermediate31 to afford Example 175.

1H NMR (300 MHz, CDCl₃, mixture of rotomers) δ: 7.58 (br t, 7.4 Hz, 3H), 7.47-7.27 (m, 6H), 6.86-6.77 (m, 3H), 4.24 (dt, J=3.0, 7.4 Hz, 2H),4.11 (br t, J=4.1 Hz, 2 H), 4.01-3.47 (m, 5.5H, rotomers), 3.87 (s, 3H),3.20 (t, J=7.4 Hz, 2H), 3.03 (d, J=9.8 Hz, 0.5 H, rotomer), 1.36/1.32(2d, J=3.6/3.7 Hz, 1H), 1.16/1.13 (2D, J=6.5/6.4 Hz, 3H), 0.74 (s, 3H).LRMS (Electrospray, positive): m/e 490 (m+H)⁺.

EXAMPLE 176

R¹=CH₂C≡CPh; R³=COCH₂OAc

2-{3((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-1-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-oxoethylAcetate

A round bottom flask equipped with a stir bar and condenser was chargedwith the compound of Example 173 (270 mg, 0.769 mmol), acetone (5 mL),CsCO₃ (376 mg, 1.15 mmol), and Intermediate 90 (242 mg, 1.15 mmol) undera nitrogen atmosphere. The mixture was refluxed for 4 hours, thenallowed to cool to room temperature. The acetone was removed underreduced pressure, and the residue taken up in EtOAc/water. The resultingmixture was extracted with EtOAc (2×100 mL), dried (Na₂SO₄), andconcentrated. Biotage purification (40 M cartridge, 1:1:.1EtOAc:hexane:-MeOH) afforded 146 mg of Example 176 as a white foam(41%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.41-7.25 (m, 5H), 7.05(dd, 1H), 6.85 (d, 2H), 5.05-4.95 (m, 2H), 4.70-4.58 (m, 2H), 3.88 (d,3H), 3.95-3.13 (c, 6H), 2.19 (s, 3H), 0.97-0.92 (dd, 3H), 0.71 (d, 3H).LRMS (Electrospray, positive): Da/e 466.4 (m+1).

EXAMPLE 177

R¹=CH₂C≡C-4-FPh; R³=COCH₂OAc

2-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)-2-oxoethylAcetate

Prepared from Example 173 by the method of Example 176 usingIntermediate 91 as the alkylating agent.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.40-7.36 (m, 2H),7.04-6.97 (m, 3H), 6.86-6.85 (m, 2H), 4.98-4.97 (m, 2H), 4.71-4.59 (m,2H), 3.88 (d, 3H), 3.96-3.16 (c, 6H), 2.20-2.18 (m, 3H), 1.01 (t, 3H),0.72 (d, 3H). LRMS (Electrospray, positive): Da/e 484.8 (m+1).

EXAMPLE 178

R¹=CH(C₃H₅)C₃H₅; R³=COCH₂OAc

2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[2-(dicyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoethylAcetate

Prepared from Example 173 by the Mitsunobu method of Example 144 usingdicyclopropylcarbinol.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.26-6.78 (m, 3H),4.74-4.60 (m, 2H), 3.96-3.46 (m, 9H), 3.21-3.10 (m, 2H), 2.20 (s, 3H),1.26 (d, 1H), 1.19-1.11 (m, 4H), 0.75 (d, 3H), 0.55-0.41 m, 4H),0.33-0.24 (m, 4H). LRMS (Electrospray, positive): Da/e 446.5 (m+1).

EXAMPLE 179

R¹=3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)methyl; R³=COCH₂OAc

2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoethylAcetate

Prepared from Example 173 via the CsCO₃ method of Example 176 usingIntermediate 87.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 8.02 (d, 2H), 7.46 (d,2H), 6.95-6.85 (m, 3H), 5.40 (d, 2H), 4.70-4.58 (m, 2H), 3.94 (d, 3H),3.95-3.12 (c, 6H), 2.19 (s, 3H), 1.04-1.00 (dd, 3H), 0.64 (d, 3H). LRMS(Electrospray, positive): Da/e 544.4 (m+1).

EXAMPLE 180

R¹=CH₂C≡CPh: R³=COCH₂OH

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one

Prepared from Example 176 via the LiOH hydrolysis procedure ofIntermediate 5.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.40-7.26 (m, 5H),7.07-7.06 (m, 1H), 6.85-6.84 (m, 2H), 5.05-4.94 (m, 2H), 3.89 (s, 3H),4.13-2.99 (c, 8H), 0.98-0.92 (dd, 3H), 0.71 (s, 3H). LRMS (Electrospray,positive): Da/e 424.6 (m+1).

EXAMPLE 181

R¹=CH₂C≡C-4-FPh; R³=COCH₂OH

1-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)-2-hydroxyethan-1-one

Prepared from Example 177 via the LiOH hydrolysis procedure ofIntermediate 5.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.39-7.36 (m, 2H),7.03-6.98 (m, 3H), 6.85 (s, 2H), 5.02-4.93 (m, 2H), 3.89 (s, 3H),4.15-3.01 (c, 8H), 1.04-0.99 (dd, 3H), 0.72 (s, 3H). LRMS (Electrospray,positive): Da/e 442.7 (m+1).

EXAMPLE 182

R¹=C₃H₅CHC₃H₅; R³=COCH₂OH

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(dicyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one

Prepared from Example 178 by the LiOH hydrolysis procedure ofIntermediate 5.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.90-6.78 (m, 3H),4.17-3.44 (c, 11H), 3.15-3.03 (m, 2H), 1.32-1.20 (m, 1H), 1.19-1.09 (m,4H), 0.75 (d, 3H), 0.54-0.39 (m, 4H), 0.34-0.23 (m, 4H). LRMS(Electrospray, positive): Da/e 404.5 (m+1).

EXAMPLE 183

R¹=3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)methyl; R³=COCH₂OH

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}-4-metihoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyethan-1-one

Prepared from Example 179 via the LiOH hydrolysis procedure ofIntermediate 5.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 8.03 (d, 2H), 7.47 (d,21), 6.95-686 (m, 3H), 5.40 (s, 2H), 3.88 (s, 3H), 4.12-2.98 (c, 8H),1.05-0.99 (dd, 3H), 0.64 (d, 3H) LRMS (Electrospray, positive): Da/e502.4 (m+1).

EXAMPLE 184

R¹=CH₂CH₂t-Bu; R³=COCH₂OCH₂Ph

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(3,3-dimethylbutoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(phenylmethoxy)ethan-1-one

Prepared from Example 143 via the Mitsunobu method of Example 144 using3,3-dimethyl-1-butanol.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.41-7.31 (m, 5H),6.80-6.75 (m, 3H), 4.70-4.63 (m, 2H), 4.15-3.21 (c, 13H), 1.80-1.73 (m,2H), 1.17-1.10 (m, 2H), 0.98 (s, 9H), 0.74 (d, 3H). LRMS (Electrospray,positive): Da/e 484.6 (m+1).

EXAMPLE 185

R¹=CH₂CH₂t-Bu; R³=COCH₂OH

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(3,3-dimethylbutoxy)-4-methoxyphenyl]3-methylpyrrolidinyl}-2-hydroxyethan-1-one

Prepared from Example 184 via the debenzylation method of Intermediate31.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.88-6.71 (m, 3H),4.38-2.99 (c, 13H), 1.82-1.73 (m, 2H), 1.19-1.08 (m, 3H), 0.97 (s, 9H),0.80-0.69 (m, 3H). LRMS (Electrospray, positive): Da/e 394.4 (m+1).

EXAMPLE 186

R¹=CH₂C₃H₅; R³=COCH₂OCH₂Ph

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(phenylmethoxy)ethan-1-one

Prepared from Intermediate 67 via the Hunig's base coupling method ofIntermediate 74 using benzyloxyacetyl chloride.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.40-7.29 (m, 5H),6.82-6.74 (m, 3H), 4.66 (s, 2H), 4.15-3.20 (c, 11H), 1.71-1.57 (br s,1H), 1.35-1.23 (m, 1H), 1.16-1.07 (dd, 3H), 0.71 (s, 3H), 0.62 (d, 2H),0.34 (d, 2H). LRMS (Electrospray, positive): Da/e 454.6 (m+1).

EXAMPLE 187

R¹=CH₂C₃H₅; R³=COCH₂OH

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one

Prepared from Example 186 via the debenzylation method of Intermediate31.

¹H NMR (Methanol-d₄, 400 MHz) δ: 6.95-6.34 (m, 3H), 4.31-4.22 (m, 2H),3.91-3.23 (c, 11H), 1.30-1.19 (m, 1H), 0.74 (S, 3H), 0.62-56 (m, 2H),0.35-0.28 (m, 2H). LRMS (Electrospray, positive): Da/e 364.2 (m+1).

EXAMPLE 188

R¹=CH₂C₃H₅; R³=COCH₂NHCO₂CH₂Ph

N-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoethyl)(phenylmethoxy)carboxamide

Prepared from Intermediate 67 via the acylation procedure of Example 7using Z-Gly-ONp.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.45-7.30 (m, 5H),6.85-6.76 (m, 3H), 5.81 (br s, 1H), 5.13 (s, 2H), 4.10-3.43 (c, 12H),3.17 (d, 1H), 1.68 (br s, 1H), 1.36-1.26 (m, 1H), 1.14 (t, 3H) 0.73 (d,3H), 0.66-0.60 (m, 2H), 0.38-0.31 (m, 2H).

EXAMPLE 189

R¹=CH₂C₃H₅; R³=COCH₂NH₂

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-aminoethan-1-one

Prepared from Example 188 via the debenzylation procedure ofIntermediate 31.

¹H NMR (Methanol-d₄, 400 MHz, mixture of rotomers) δ: 6.96-6.81 (m, 3H),4.00-3.27 (c, 13H), 1.29-1.18 (m, 1H), 1.13-1.07 (m, 3H), 0.75 (m, 3H),0.62-54 (m, 2H), 0.35-0.28 (m, 2H). LRMS (Electrospray, positive): Da/e363.2 (m+1).

EXAMPLE 190

R¹=CH₂C₃H₅; R³=COC(CH₃)₂OCOCH₃

2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1,1-dimethyl-2-oxoethylAcetate

Prepared from Intermediate 67 via the Hunig's base coupling procedure ofIntermediate 74 using 2-acetoxyisobutyryl chloride.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.87-6.70 (m, 3H),3.93-3.32 (c, 11H), 2.08 (d, 3H), 1.81-1.65 (br m, 1H), 1.65-1.53 (m,6H), 1.35-1.23 (m, 1H), 1.19-1.11 (t, 3H), 0.68 (d, 3H), 0.65-0.57 (m,2H), 0.37-0.30 (m, 2H).

EXAMPLE 191

R¹=CH₂C₃H₅; R³=COC(CH₃)₂OH

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxy-2-methylpropan-1-one

Prepared from Example 190 via the LiOH hydrolysis procedure ofIntermediate 5.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.84-6.75 (m, 3H), 4.43(br s, 1H), 4.01-3.41 (c, 11H), 1.52-1.41 (m, 6H), 1.32-1.17 (m, 1H),1.16-1.08 (t, 3H), 0.73 (d, 3H), 0.63-0.57 (m, 2H), 0.37-0.29 (m, 2H).LRMS (Electrospray, positive): Da/e 392.5 (m+1).

EXAMPLE 192

R¹=CH₂C₃H₅; R³=(S)—COCH(CH₃)OAc

2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-methyl-2-oxoethylAcetate

Prepared from Intermediate 67 via the Hunigis base coupling procedure ofIntermediate 74 using (S)-2-acetoxypropionyl chloride.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.83-6.76 (m, 3H),5.25-5.17 (m, 1H), 4.08-3.35 (c, 12H), 2.15-2.09 (m, 3H), 1.50-1.44 (m,3H), 1.35-1.23 (m, 1H), 1.15 (d, 3H), 0.79-0.71 (m, 3H), 0.65-0.60 (m,2H), 0.37-0.30 (m, 2H).

EXAMPLE 193

R¹=CH₂C₃H₅; R³=(S)—COCH(CH₃)OH

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxypropan-1-one

Prepared from Example 192 via the LiOH hydrolysis procedure ofIntermediate 5.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.84-6.73 (m, 3H),4.39-4.28 (m, 1H), 3.88-3.48 (c, 10H), 3.29 (dd, 1H), 1.40-1.20 (m, 4H),1.12 (t, 3H), 0.73 (d, 3H), 0.64-0.55 (m, 2H), 0.37-0.29 (m, 2H). LRMS(Electrospray, positive): Da/e 378.7 (m+1).

EXAMPLE 194

R¹=CH₂C₃H₅; R³=COCH(Ph)OAc

2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxo-1-phenylethylAcetate

Prepared from Intermediate 67 via the Hunig's base coupling procedure ofIntermediate 74 using O-acetylmandelic acid chloride.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers and diastereomers) δ:7.57-7.35 (m, 5H), 6.84-6.51 (m, 3H), 6.11-6.04 (m, 1H), 4.08-3.05 (c,11H), 2.21-2.14 (m, 3H), 1.36-1.20 (m, 1H), 1.14-1.06 (dd, 3H), 0.78 and0.48 (s and d, 3H), 0.67-0.57 (m, 2H), 0.37-0.28 (m, 2H). LRMS(Electrospray, positive): Da/e 482.6 (m+1).

EXAMPLE 195

R¹=CH₂C₃H₅; R³=COCH(Ph)OH

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxy-2-phenylethan-1-one

Prepared from Example 194 via the LiOH hydrolysis procedure ofIntermediate 5.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers and diastereomers) δ:7.40-7.28 (m, 5H), 6.81-6.42 (m, 3H), 5.13-4.61 (m, 1H), 4.07-3.29 (c,10H), 3.21-2.79 (m, 1H) 1.36-1.20 (m, 1H), 1.15-0.97 (dd, 3H), 0.73 and0.47 (d and s, 3H), 0.65-0.56 (m, 2H), 0.37-0.28 (m, 2H). LRMS(Electrospray, positive): Da/e 440.2 (m+1).

EXAMPLE 196

R¹=CH₂C₃H₅; R³=COCH(4-FPh)OAc

2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-(4-fluorophenyl)-2-oxoethylAcetate

Prepared from Intermediate 67 via the Hunig's base coupling procedure ofIntermediate 74 using (chlorocarbonyl)(4-fluorophenyl)methyl acetate.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers and diastereomers) δ:7.60-7.46 (m, 2H), 7.15-7.03 (m, 2H), 6.85-6.54 (m, 3H), 6.09-5.99 (m,1H), 4.07-2.87 (c, 11H), 2.19-2.12 (m, 3H), 1.33-1.20 (m, 1H), 1.15-1.03(dd, 3H), 0.78 and 0.52 (d and d, 3H), 0.65-0.57 (m, 2H), 0.38-0.27 (m,2H). LRMS (Electrospray, positive): Da/e 501.0 (m+1).

EXAMPLE 197

R¹=CH₂C₃H₅; R³=COCH(4-FPh)OH

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(4-fluorophenyl)-2-hydroxyethan-1-one

Prepared from Example 196 via the LiOH hydrolysis procedure ofIntermediate 5.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers and diastereomers) δ:7.60-7.25 (m, 2H), 7.12-7.00 (m, 2H), 6.84-6.48 (m, 3H), 5.11-4.59 (m,1H), 4.04-2.79 (c, 11H), 1.35-1.23 (m, 1H), 1.15-1.00 (dd, 3H), 0.75 and0.48 (d and s, 3H), 0.66-0.60 (m, 2H), 0.37-0.30 (m, 2H). LRMS(Electrospray, positive): Da/e 458.2 (m+1).

EXAMPLE 198

R¹=CH₂C₃H₅; R³=COC(CH₂CH₂)OAc

({3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-carbonyl)cyclopropylAcetate

Prepared from Intermediate 67 via the Hunig's base coupling procedure ofIntermediate 74 using (chlorocarbonyl)cyclopropyl acetate.

¹H NMR (400 MHz, CDCl₃) δ: 6.85-6.72 (m, 3H), 4.06-3.31 (c, 11H), 2.10(s, 3H), 1.74-1.62 (m, 1H), 1.59-1.47 (m, 1H), 1.35-1.19 (m, 2H), 1.14(d, 3H), 1.02-0.93 (m, 1H), 0.71 (s, 3H), 0.65-0.59 (m, 2H), 0.37-0.30(m, 2H). LRMS (Electrospray, positive): Da/e 432.5 (m+1).

EXAMPLE 199

R¹=CH₂C₃H₅; R³=COC(CH₂CH₂)OH

3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinylHydroxycyclopropyl Ketone

Prepared from Example 198 via the LiOH hydrolysis procedure ofIntermediate 5.

¹H NMR (400 MHz, CDCl₃) δ: 6.88-6.78 (m, 3H), 4.42-3.30 (c, 11H),1.42-1.22 (m, 3H), 1.16 (d, 3H), 1.11-0.88 (m, 3H), 0.74 (d, 3H),0.66-0.59 (m, 2H), 0.39-0.31 (m, 2H). LRMS (Electrospray, positive):Da/e 390.5 (m+1).

EXAMPLE 200

R¹=CH₂C₃H₅; R³=(S)—COCH(OAc)CH(CH₃)CH₂CH₃

2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-(methylpropyl)-2-oxoethylAcetate

Prepared from Intermediate 67 via the Hunig's base coupling procedure ofIntermediate 74 using (1S)-1-(chlorocarbonyl)-2-methylbutyl acetate.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers and diastereomers) δ:6.85-6.72 (m, 3H), 4.84 (dd, 1H), 3.89-3.31 (c, 11H), 2.12 (d, 3H),2.09-1.95 (m, 1H), 1.75-1.62 (m, 1H), 1.35-1.19 (m, 2H), 1.15 (t, 3H),1.00-0.86 (m, 6H), 0.75 (d, 3H), 0.65-0.56 (m, 2H), 0.37-0.30 (m, 2H).LRMS (Electrospray, positive): Da/e 462.5 (m+1).

EXAMPLE 201

R¹=CH₂C₃H₅; R³=(S)—COCH(OH)CH(CH₃)CH₂CH₃

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxy-3-methylpentan-1-one

Prepared from Example 200 via the LiOH hydrolysis procedure ofIntermediate 5.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers and diastereomers) δ:6.85-6.76 (m, 3H), 4.18-4.11 (m, 1H), 3.94-3.26 (c, 11H), 1.75-1.66 (m,1H), 1.54-1.19 (m, 4H), 1.15 (dd, 3H), 1.07 (m, 3H), 0.94-0.85 (m, 3H),0.76 (d, 3H), 0.66-0.60 (m, 2H), 0.38-0.32 (m, 2H). LRMS (Electrospray,positive): Da/e 420.5 (m+1).

EXAMPLE 202

R¹=CH₂C₃H₅; R³=(S)—COCH(OAc)CH₂CH(CH₃)₂

2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-(2-methylpropyl)-2-oxoethylAcetate

Prepared from Intermediate 67 via the Hunig's base coupling procedure ofIntermediate 74 using (1S)-1-(chlorocarbonyl)-3-methylbutyl acetate.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.84-6.74 (m, 3H),5.19-5.10 (m, 1H), 4.15-2.95 (c, 11H), 2.13 (d, 3H), 1.95-1.72 (m, 2H),1.58-1.39 (m, 2H), 1.34-1.23 (m, 1H), 1.18-1.12 (m, 3H), 1.00-0.88 (m,6H), 0.75 (d, 3H), 0.68-0.57 (m, 2H), 0.37-0.30 (m, 2H). LRMS(Electrospray, positive): Da/e 462.5 (m+1).

EXAMPLE 203

R¹=CH₂C₃H₅; R³=(S)—COCH(OH)CH₂CH(CH₃)₂

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxy-4-methylpentan-1-one

Prepared from Example 202 via the LiOH hydrolysis procedure ofIntermediate 5.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.86-6.77 (m, 3H),4.32-4.25 (m, 1H), 3.88-2.97 (c, 11H), 2.05-1.93 (m, 1H), 1.73-1.21 (m,5H), 1.14 (dd, 3H), 1.02-0.93 (m, 6H), 0.76 (d, 3H), 0.66-0.60 (m, 2H),0.38-0.32 (m, 2H). LRMS (Electrospray, positive): Da/e 420.3 (m+1).

EXAMPLE 204

R¹=CH₂C₃H₅; R³=(S)—COCH(OAc)CH₂Ph

2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-2-oxo-1-benzylethylAcetate

Prepared from Intermediate 67 via the Hunig's base coupling procedureusing (1S)-1-(chlorocarbonyl)-2-phenylethyl acetate.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.40-7.26 (m, 5H),6.82-6.70 and 6.52-6.47 (m and m, 3H), 5.30-5.18 (m, 1H), 3.90-2.79 (c,13H), 2.11 (d, 3H), 1.35-1.25 (m, 1H), 1.05 (dd, 3H), 0.66 and 0.33 (sand s, 3H), 0.68-0.60 (m, 2H), 0.39-0.32 (m, 2H). LRMS (Electrospray,positive): Da/e 497.0 (m+1).

EXAMPLE 205

R¹=CH₂C₃H₅; R³=(S)—COCH(OH)CH₂Ph

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxy-3-phenylpropan-1-one

Prepared from Example 204 (20 mg, 0.040 mmol) by the LiOH hydrolysisprocedure of Intermediate 5 to afford 14.5 mg (79%) of Example 205 as acolorless film.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.40-7.26 (m, 5H),6.82-6.75 and 6.56-6.53 (m and m, 3H), 4.51-4.43 (m, 1H), 3.90-2.70 (c,13H), 1.35-1.25 (m, 1H), 1.09 (dd, 3H), 0.69 and 0.52 (s and s, 3H),0.68-0.60 (m, 2H), 0.39-0.32 (m, 2H). LRMS (Electrospray, positive):Da/e 454.3 (m+1).

EXAMPLE 206

R¹=CH₂C₃H₅; R³=(R)—COCH(OAc)CH₂Ph

(1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxo-1-benzylethylAcetate

Prepared from Intermediate 67 via the Hunig's base coupling procedure ofIntermediate 74 using (1R)-1-(chlorocarbonyl)-2-phenylethyl acetate.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.37-7.22 (m, 5H),6.82-6.72, 6.64, 6.45 (m, d, and dd, 3H), 5.27 and 5.18 (dd, t, 1H),3.99-2.56 (c, 13H), 2.12 (s, 3H), 1.34-1.24 (m, 1H), 1.13-1.02 (dd, 3H),0.68 and 0.34 (s and s, 3H), 0.65-0.58 (m, 2H), 0.37-0.30 (m, 2H). LRMS(Electrospray, positive): Da/e 496.6 (m+1).

EXAMPLE 207

R¹=CH₂C₃H₅; R³=(R)—COCH(OH)CH₂Ph

((2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxy-3-phenylpropan-1-one

Prepared from Example 206 via the lithium peroxide method ofIntermediate 43.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.35-7.18 (m, 5H),6.84-6.67 (m, 3H), 4.48-4.40 (m, 1H), 4.04-2.70 (c, 13H), 1.34-1.24 (m,1H), 1.08 (dd, 3H), 0.71 and 0.49 (s and s, 3H), 0.65-0.58 (m, 2H),0.38-0.31 (m, 2H). LRMS (Electrospray, positive): Da/e 454.5 (m+1).

EXAMPLE 208

R¹=t-Bu; R³=(S)—COCH(OAc)CH₃

2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-methyl-2-oxoethylAcetate

Prepared from Intermediate 73 via the. Hunig's base coupling procedureof Intermediate 74 using (S)-2-acetoxypropionyl chloride.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.95-6.81 (m, 3H),5.24-5.11 (m, 1H), 3.80 (m, 3H), 4.08-3.38 (m, 6H), 2.15-2.12 (d, 3H),1.49-1.46 (dd, 3H), 1.33 (d, 9H), 1.14 (d, 3H), 0.76 (d, 3H). LRMS(Electrospray, positive): Da/e 422.4 (m+1).

EXAMPLE 209

R¹=H; R³=(S)—COCH(OAc)CH₃

2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-1-methyl-2-oxoethylAcetate

Prepared from Example 208 via the TFA deprotection method of Example143.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.88-6.70 (m, 3H),5.73-5.69 (br d, 1H), 5.25-5.19 (m, 1H), 3.88 (d, 3H), 4.06-3.38 (m,6H), 2.12 (d, 3H), 1.49-1.46 (d, 3H), 1.16-1.14 (dd, 3H), 0.75 (d, 3H).LRMS (Electrospray, positive): Da/e 366.3 (m+1).

EXAMPLE 210

R¹=CH₂C≡CPh; R³=(S)—COCH(OAc)CH₃

2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-(1S)-1-methyl-2-oxoethylAcetate

Prepared from Example 209 via the Cs₂CO₃ method of Example 176 usingIntermediate 90.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.39-7.26 (m, 5H), 7.05(d, 1H), 6.85 (s, 2H), 5.23-5.17 (m, 1H), 5.05-4.95 (m, 2H), 3.86 (s,3H), 4.07-3.36 (d, 6H), 2.15-2.12 (d, 3H), 1.47-1.40 (t, 3H), 1.36-1.33(m, 1H), 0.99-0.95 (m, 3H), 0.75-0.71 (d, 3H). LRMS (Electrospray,positive): Da/e (m+1).

EXAMPLE 211

R¹=CH₂C≡CPh; R³=(S)—COCH(OH)CH₃

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-(2S)-2-hydroxypropan-1-one

Prepared from Example 210 via the O-acetate deprotection method ofExample 95.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.41-7.26 (m, 5H), 7.07(d, 1H), 6.86 (s, 2H), 5.05-4.94 (m, 1H), 4.36-4.30 (m, 1H), 3.89 (s,3H), 3.91-3.48 (c, 5H), 3.28 (dd, 1H), 1.37-1.32 (m, 3H), 0.99-0.92 (dd,3H), 0.73-0.70 (d.3H). LRMS (Electrospray, positive): Da/e 438.2 (m+1).

EXAMPLE 212

R¹=CH₂C≡C-4-FPh; R³=(S)—COCH(OAc)CH₃

2-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)-2-oxoethylAcetate

Prepared from Example 209 via the Cs₂CO₃ method of Example 176 usingIntermediate 91.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.40-7.36 (m, 2H),7.03-6.96 (m, 3H), 5.22-5.20 (q, 1H), 4.98-4.96 (m, 2H), 4.07-3.53 (c,6H), 3.88-3.86 (m, 3H), 2.14-2.11 (d, 3H), 1.47-1.42 (t, 3H), 1.06-1.01(m, 3H), 0.75-0.72 (d, 3H). LRMS (Electrospray, positive): Da/e 498.5(m+1).

EXAMPLE 213

R¹=CH₂C≡C-4-FPh; R³=(S)—COCH(OH)CH₃

1-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methyl-pyrrolidinyl)(2S)-2-hydroxypropan-1-one

Prepared from Example 212 via the O-acetate deprotection method ofExample 95.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.40-7.26 (m, 2H),7.04-6.98 (m, 3H), 6.86 (s, 2H), 5.03-4.97 (m, 2H), 4.40-4.30 (m, 1H),3.89 (s, 3H), 3.94-3.52 (c, 5H), 3.29 (dd, 1H), 1.39-1.28 (d, 3H),1.04-1.00 (m, 3H), 0.74-0.72 (d, 3H). LRMS (Electrospray, positive):Da/e 456.5 (m+1).

EXAMPLE 214

R¹=CH₂C≡C-4-CF₃Ph; R³=(S)—COCH(OAc)CH₃

2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(4-methoxy-3-{3-[4-(trifluoromethyl)phenyl]prop-2-ynyloxy}phenyl)-3-methylpyrrolidinyl](1S)-1-methyl-2-oxoethylAcetate

Prepared from Example 209 via the Cs₂CO₃ method of Example 176 usingIntermediate 92.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.57-7.45 (m, 4H), 7.01(d, 1H), 6.88-6.83 (m, 2H), 5.22-5.17 (m, 1H), 5.00 (s, 2H), 4.07-3.35(c, 6H), 3.88 (d, 3H), 2.13-2.11 (d, 3H), 1.47-1.42 (dd, 3H), 1.12 (d,3H), 0.75-0.71 (d, 3H). LRMS (Electrospray, positive): Da/e 548.8 (m+1).

EXAMPLE 215

R¹=CH₂C≡C-4-CF₃Ph; R³=(S)—COCH(OH)CH₃

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(4-methoxy-3-{3-[4-(trifluoromethyl)phenyl]prop-2-ynyloxy}phenyl)-3-methylpyrrolidinyl](2S)-2-hydroxypropan-1-one

Prepared from Example 214 via the O-acetate deprotection method ofExample 95.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.56 (d, 2H), 7.50 (d,2H), 7.03 (s, 1H), 6.87 (s, 2H), 5.01 (s, 2H), 4.36-4.33 (m, 1H), 3.89(s, 3H), 3.91-3.49 (c, 5H), 3.30 (dd, 1H), 1.37-1.35 (dd, 3H), 1.04-1.01(t, 3H), 0.74-0.71 (d, 3H). LRMS (Electrospray, positive): Da/e 505.9(m+1).

EXAMPLE 216

R¹=3-(4-Chlorophenyl)(1,2,4-oxadiazol-5-yl)methyl; R³=(S)—COCH(OAc)CH₃

2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-1-methyl-2-oxoethylAcetate

Prepared from Example 209 via the Cs₂CO₃ method of Example 176 usingIntermediate 87.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 8.01 (d, 2H), 7.46 (d,1H), 6.96-6.85 (m, 3H), 5.45-5.36 (m, 2H), 5.21-5.14 (m, 1H), 4.02-3.36(c, 6H), 3.84 (m, 3H), 2.11 (d, 3H), 1.47-1.42 (m, 3H), 1.04-1.02 (d,3H), 0.67-0.65 (d, 3H). LRMS (Electrospray, positive): Da/e 558.2 (m+1).

EXAMPLE 217

R¹=3-(4-Chlorophenyl)(1,2,4-oxadiazol-5-yl)methyl; R³=(S)—COCH(OH)CH₃

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-hydroxypropan-1-one

Prepared from Example 216 via the O-acetate deprotection method ofExample 95.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 8.06-8.00 (m, 2H),7.49-7.45 (m, 2H), 6.97-6.86 (m, 3H), 5.41 (m, 2H), 4.35-4.32 (m, 1H),3.88 (s, 3H), 3.35-3.19 (c, 6H), 1.33-1.32 (m, 3H), 1.05-1.00 (dd, 3H),0.66-0.63 (d, 3H). LRMS (Electrospray, positive): Da/e 516.4 (m+1).

EXAMPLE 218

R¹=2-Indanyl; R³=COCH(OAc)4-FPh

2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yl-oxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-(4-fluorophenyl)-2-oxoethylAcetate

Intermediate 51 (72.8 mg, 0.198 mmol) was acylated by the K₂CO₃procedure of Example 7 with 2-acetoxyfluoromandelic acid chloride (120mg, 0.297 mmol, 1.5 eq) to give a clear, colorless oil (84.2 mg, 75%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.53-7.47 (m, 2H),7.26-7.03 (m, 6H), 6.87-6.59 (m, 3H), 6.09-6.04 (m, 1H), 5.28-5.01 (m,1H), 4.14-3.03 (c, 13H), 2.16 (s, 3H), 1.27-1.06 (m, 3H), 0.82-0.80 (d,1.5H), 0.55-0.52 (d, 1.5H).

EXAMPLE 219

R¹=2-Indanyl; R³=COCH(OH)4-FPh

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(4-fluorophenyl)-2-hydroxyethan-1-one

Example 218 (19 mg, 0.034 mmol, 1 eq) was subjected to the LiOHhydrolysis procedure of Intermediate 5 to yield a white powder (6.1 mg,35%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.97-6.80 (c, 7H), 4.19(m, 2H), 4.13 (t, 2H), 3.82 (s, 3H), 3.72 (s, 3H), 3.83-3.48 (c, 4H),3.25 (dd, 1H), 2.27 (quintet, 2H), 1.70 (s, 1H), 1.56 (br d, 1H), 1.13(t, 3H), 0.73(s, 3H). LRMS (Electrospray, positive): Da/e 520.4 (m+1).

EXAMPLE 220

R¹=2-Indanyl; R³=COCH(OAc)CH₃

2-[(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-methyl-2-oxoethylAcetate

Intermediate 51 (27 mg, 0.074 mmol) was acylated by the K₂CO₃ procedureof Example 7 using (+)-2-acetoxypropionyl chloride (12.1 μL, 0.110 mmol,1.5 eq) to yield a clear, colorless oil (16.7 mg, 47%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.27-7.17 (m, 4H),6.85-6.83 (m, 3H), 5.30-5.17 (m, 2H), 4.13-3.19 (c, 9H), 2.14 (s, 3H),1.72 (br s, 1H), 1.51-1.47 (m, 4H), 1.19-1.17 (d, 3H), 0.82-0.78 (d,3H).

EXAMPLE 221

R¹=2-Indanyl; R³=COCH(OH)CH₃

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxypropan-1-one

Example 220 (16.7 mg, 0.0347 mmol, 1 eq) was subjected to the LiOHhydrolysis procedure of Intermediate 5 to yield a white solid (4.7 mg,31%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.27-7.17 (m, 4H),6.85-6.84 (m, 3H), 5.19-5.15 (m, 1H), 4.39-4.35 (m, 1H), 3.90-3.18 (c,14H), 1.57-1.37 (m, 3H), 1.28-1.15 (m, 3H), 0.80-0.78 (d, 3H). LRMS(Electrospray, positive): Da/e 440.4 (m+1).

EXAMPLE 222

R¹=2-Indanyl; R³=COC(CH₃)(OAc)CH₃

2-[(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1,1-dimethyl-2-oxoethylAcetate

Intermediate 51 (40 mg, 0.11 mmol) was acylated by the K₂CO₃ procedureof Example 7 using 2-acetoxy-2-methhylpropionyl chloride (31 μL, 0.22mmol, 2 eq) to yield a clear, colorless oil (22 mg, 40%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.26-7.16 (m, 4H),6.85-6.77 (m, 3H), 4.17 (m, 1H), 3.95-3.19 (c, 14H), 2.10 (s, 3H),1.65-1.57 (m, 6H), 1.20-1.17 (m, 3H), 0.73 (s, 3H).

EXAMPLE 223

R¹=2-Indanyl; R³=COC(CH₃)(OH)CH₃

1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxy-2-methylpropan-1-one

Example 222 (22 mg, 0.044 mmol) was subjected to the LiOH hydrolysisprocedure of Intermediate 5 to yield product as a white solid (4.3 mg,22%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.26-7.17 (m, 4H), 6.83(m, 3H), 5.18-5.17 (m, 1H), 4.45-4.44 (m, 1H), 3.89-3.19 (c, 14H),1.53-1.48 (m, 6H), 1.19-1.17 (m, 3H), 0.79-0.78 (d, 3H). LRMS(Electrospray, positive): Da/e 454.4 (m+1).

EXAMPLE 224

R¹=t-Bu; R³=CO₂CH₃

Methyl(3R)-3-((1R)-1-hydroxyethyl)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylate

Intermediate 73 (6.5 μL, 0.084 mmol) was acylated by the Hunig's basemethod of Intermediate 74 with methyl chloroformate to provide Example224 as a yellow oil (19 mg, 94%).

¹H-NMR (400 MHz, CDCl₃) δ: 6.96 (d, 1H), 6.84 (s, 1H), 6.83 (d, 1H),3.80 (s, 3H), 3.77-3.58 (m, 4H), 3.06 (d, 1H), 1.36 (s, 9H), 1.16 (d,3H), 0.76 (s, 3H).

EXAMPLE 2252-Hydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[2-(tetrahydrofuran-2-yl)ethoxy]phenyl}-3-methylpyrrolidin-1-yl)ethanone

Prepared from Example 143 by the Mitsunobu procedure of Example 144using 2-tetrahydrofuran-2-ylethanol followed by debenzylation via themethod of Intermediate 31.

¹H NMR data δ: 6.75-6.87 (m, 3H); 4.16-4.20 (m, 2H) 4.15 (S, 3H);3.49-4.13 (m, 11H); 3.05 (d, 1H); 1.97-2.10 (m, 2H)1.88-1.96 (t, 2H);1.56-1.63 (m, 2H); 1.3-1.17 (t, 3H); 0.75 (s, 3H).

EXAMPLE 2262-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxy-ethyl)-4-[4-methoxy-3-(tetrahydrofuran-3-ylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

Prepared from Example 143 by the Mitsunobu method of Example 144 usingtetrahydrofuran-3-ylMethanol followed by the debenzylation procedure ofIntermediate 31.

¹H NMR data δ: 6.79-6.82 (m, 3H); 4.13-4.16 (m, 2H); 3.48-3.98 (m, 11H);3.84 (s, 3H); 3.05 (d, 1H); 2.80 (bt; 1H); 2.07-2.15 (M, 2H); 1.72-1.79(m, 1H); 1.16 (t, 3H); 0.76 (s, 3H).

EXAMPLE 227

R¹=(S)—CH(CH₂OCH₂CH₂); R³=CO₂CH₃

Methyl(3R)-3-((1R)-1-Hydroxyethyl)-4-[3-((3S)-oxolan-3-yloxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylate

Prepared from Intermediate 74 (146 mg, 0.47 mmol) by the solid phaseMitsunobu procedure of Example 144 using(S)-(+)-3-hydroxytetrahydrofuran (38 μL), 0.47 mmol) to afford Example227 as a clear oil (95 mg, 53%).

¹H-NMR (400 MHz, CDCl₃) δ: 6.82 (m, 2H), 6.78 (m, 1H), 4.95 (m, 1H),4.03-3.20 (m, 10H), 3.82 (s, 3H), 3.66 (s, 3H), 2.17 (m, 2H), 1.17 (t,3H), 0.73 (s, 3H). LRMS (Electrospray, positive): Da/e 379.8 (m+1).

EXAMPLE 228

R¹=(R)—CH(CH₂OCH₂CH₂); R³=CO₂CH₃

Methyl(3R)-3-((1R)-1-Hydroxyethyl)-4-[3-((3R)-oxolan-3-yloxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylate

Prepared from Intermediate 74 using the solid phase Mitsunobu reactionof Example 144 and (R)-(−)-3-hydroxytetrahydrofuran (46 μL), 0.57 mmol)to give Example 228 as a clear oil (27 mg, 37%).

¹H-NMR (400 MHz, CDCl₃) δ: 6.82 (m, 2H), 6.78 (m, 1H), 4.95 (m, 1H),4.03-3.20 (m, 10H), 3.82 (s, 3H), 3.66 (s, 3H), 2.17 (m, 2H), 1.17 (t,3H), 0.73 (s, 3H). LRMS (Electrospray, positive): Da/e 380.3 (m+1).

EXAMPLE 229

R¹=CH₂CH₂O-4-FPh; R³=CO₂CH₃

Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-{3-[2-(4-fluorophenoxy)ethoxy]-4-methoxyphenyl}-3-methylpyrrolidinecarboxylate

Prepared by the K₂CO₃ etherification procedure of Example 43 usingIntermediate 74 (21.2 mg, 0.0685 mmol, 1 eq) and 4-fluorophenoxyethylbromide (60 mg, 0.27 mmol, 4.0 eq), yielding a clear, colorless oil(15.2 mg, 49.7%)

¹H NMR (400 MHz, CDCl₃) δ: 6.99-6.83 (c, 7H), 4.35 (t, 2H), 4.29 (t,2H), 3.83 (s, 3H), 3.72 (s, 3H), 3.83-3.48 (c, 4H), 3.25 (dd, 1H), 1.64(s, 1H), 1.42 (br d, 1H), 1.13 (t, 3H), 0.73(s, 3H).

EXAMPLE 230

R¹=CH₂CH₂CH₂O-4-FPh; R³=CO₂CH₃

Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenoxy)propoxy]-4-methoxyphenyl}-3-methylpyrrolidinecarboxylate

Prepared from Intermediate 74 (25.2 mg, 0.0815 mmol, 1 eq) by the K₂CO₃etherification procedure of Example 43 using1-(3-chloropropoxy)-4-fluorobenzene (62 mg, 0.33 mmol, 4.0 eq) to yieldExample 230 as a clear, colorless oil (19.0 mg, 50.5%).

¹H NMR (400 MHz, CDCl₃) δ: 6.97-6.80 (c, 7H), 4.19 (m, 2H), 4.13 (t,2H), 3.82 (s, 3H), 3.72 (s, 3H), 3.83-3.48 (c, 4H), 3.25 (dd, 1H), 2.27(quintet, 2H), 1.70 (s, 1H), 1.56 (br d, 1H), 1.13 (t, 3H), 0.73(s, 3H).

EXAMPLE 231

R¹=CH₂C≡CH; R³=Co₂CH₃

Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(4-methoxy-3-prop-2-ynyloxyphenyl)-3-methylpyrrolidinecarboxylate

Prepared from Intermediate 74 via the K₂CO₃ etherification procedure ofExample 43 using propargyl bromide.

¹H NMR (400 MHz, CDCl₃) δ: 6.97 (s, 1H), 6.87-6.82 (m, 2H), 4.76 (s,2H), 3.86 (s, 3H), 3.73 (s, 3H), 3.90-3.55 (m, 5H), 3.27 (dd, 1H), 2.48(s, 1H), 1.49-1.46 (m, 1H), 1.14 (t, 3H), 0.75 (s, 3H). LRMS(Electrospray, positive): Da/e 348.1 (m+1).

EXAMPLE 232

R¹=CH₂C≡CCH₃; R³=CO₂CH₃

Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-but-2-ynyloxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylate

Prepared from Intermediate 74 via the K₂CO₃ etherification procedure ofExample 43 using 1-bromo-2-butyne.

¹H NMR (400 MHz, CDCl₃) δ: 6.96 (s, 1H), 6.85-6.82 (m, 2H), 4.72-4.71(m, 2H), 3.86 (s, 3H), 3.72 (s, 3H), 3.90-3.55 (m, 5H), 3.27 (dd, 1H),2.48 (s, 1H), 1.81 (s, 3H), 1.52-1.48 (m, 1H), 1.14 (t, 3H), 0.77(s,3H). LRMS (Electrospray, positive): Da/e 362.2 (m+1).

EXAMPLE 233

R¹=CH₂C≡CPh; R³=CO₂CH₃

Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinecarboxylate

Prepared from Intermediate 74 by the Mitsunobu reaction of Example 144using 3-phenyl-2-propyn-1-ol.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.41-7.38 (m, 2H),7.32-7.27 (m, 3H), 7.07 (d, 1H), 6,84 (s, 2H), 5.00-4.94 (m, 2H), 3.88(st 3H), 3.72 (s, 3H), 3.80-3.69 (m, 3H), 3.57-3.50 (m, 2H), 3.23 (dd,1H), 1.35-1.32 (m, 1H), 0.98-0.94 (dd, 3H), 0.70(d, 3H). LRMS(Electrospray, positive): Da/e 424.2 (m+1).

EXAMPLE 234

R¹=CH₂C≡C-4-FPh; R³=CO₂CH₃

Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinecarboxylate

Prepared from Intermediate 74 via the solid phase Mitsunobu procedure ofExample 144 using Intermediate 89.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.40-7.36 (m, 2H),7.04-6.97 (m, 3H), 6.85 (s, 2H), 4.97 (s, 2H), 3.88 (s, 3H), 3.72 (s,3H), 3.86-3.65 (m, 3H), 3.58-3.48 (m, 2H), 3.24 (dd, 1H), 1.013 (t, 3H),1.14 (t, 3H), 0.71 (d, 3H). LRMS (Electrospray, positive): Da/e 442.5(m+1).

EXAMPLE 235

R¹=CH₂C≡CPh; R³=COCH₂SAc

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-acetylthioethan-1-one

Prepared from Example 118 (30 mg, 0.082 mmol, 1.0 eq) by the Cs₂CO₃procedure of Example 176 using phenylpropargyl mesylate (17.4 mg, 0.082mmol, 1.0 eq, yielding a clear, colorless oil (13.2 mg, 33%).

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.45-6.86 (m, 8H),4.13-3.49 (c, 12H), 2.31 (s, 3H), 1.60 (s, 1H), 1.28-1.24 (dd, 1H),1.15-1.08 (dd, 3H), 0.73 (S, 3H).

EXAMPLE 236

R¹=CH₂C≡CPh; R³=COCH₂SH

1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-sulfanylethan-1-one

Prepared from Example 235 (13.2 mg, 0.0274 mmol) by the LiOH hydrolysisprocedure of Intermediate 5 to give a clear, colorless oil (10.5 mg,87%).

¹H NMR (CD₃OH, 400 MHz, mixture of rotomers) δ: 7.41-7.20 (m, 5H),6.91-6.75(m, 3H), 4.01-3.29 (c, 12H), 3.21 (s, 1H), 1.88 (s, 1H),1.38-1.21 (m, 1H), 1.07-1.03 (m, 3H), 0.73-0.72 (m, 3H). LRMS(Electrospray, positive): Da/e 440.4 (m+1).

INTERMEDIATE 93{2-[(3S,4S)-3-((R)-1-Hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidin-1-yl]-2-oxo-ethyl)carbamicAcid tert-Butyl Ester

To a flask containing a solution of Intermediate 70 (67.2 mg, 0.27 mmol)in dioxane (2.0 mL) was added a 1.0 M solution of aqueous K₂CO₃ (1.0 mL,1.0 mmol) A solution of N-Boc-glycine p-nitrophenyl ester (236 mg, 0.79mmol) in dioxane (100 mL) was added via syringe to the mixture. Themixture was stirred at room temperature for 30 minutes. The reaction wasdiluted with EtOAc (100 mL), then washed with aqueous NaHCO₃ (3×50 mL)and with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated invacuo to yield a yellow powder (43 mg. 84% yield).

¹H NMR (CDCl₃, 300 MHz, mixture of rotamers) δ: 6.88-6.77 (m, 2H,aromatic), 6.75-6.65 (m, 1H, aromatic), 5.56 (br, s, 1H, NH), 4.07-3.83(m, 3H), 3.69 (s, 3H, OMe), 3.82-3.68 (m, 2H), 3.67-3.52 (m, 2H), 3.46(d, 1H, J=11.5 Hz), 3.19 (d, 1H, J=11.5 Hz), 1.46 (s, 9H), 1.16-1.05 (m,3H), 0.74 (d, 3H). LRMS (Electrospray, positive): Da/e 353.151 (m+1).

EXAMPLE 2372-Amino-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[3-(4-trifluoromethylphenyl)-prop-2-ynyloxy]phenyl}-3-methylpyrrolidin-1-yl)ethanone

Prepared from Intermediate 93 by the Cs₂CO₃ method of Example 176 fromthe procedure of Example 109 to provide the product as an amber oil(12.7 mg, 4.1% yield).

¹H NMR (CDCl₃, 300 MHz, mixture of rotomers) δ: 7.55-7.4 (m, 4H,aromatic), 7.02 (s, 1H, aromatic), 6.85-6.7 (m, 2H, aromatic), 4.96 (s,2H), 4.38 (br. s, 2H), 4.0-3.4 (m, 7H), 3.83 (d, 3H, OMe), 3.2 (dd, 1H),1.0-0.88 (m, 3H), 0.65 (m, 3H). LRMS (Electrospray, positive): Da/e491.20 (m+1).

EXAMPLE 238

R¹=t-Bu; R³=COCO₂CH₃

Methyl2-(3-{(1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoacetate

Prepared from Intermediate 73 via the Hunig's base coupling procedure ofIntermediate 74 using methyl oxalyl chloride.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.93-6.81 (m, 3H),4.01-3.44 (c, 12H), 1.32 (s, 9H), 1.16-1.12 (dd, 3H), 0.77-0.74 (d, 3H).LRMS (Electrospray, positive): Da/e 394.0 (m+1).

EXAMPLE 239

R¹=H; R³=COCO₂CH₃

Methyl2-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoacetate

Prepared from Example 238 via the TFA deprotection method of Example143.

¹H NMR (400 MHz, CDCl₃₁, mixture of rotomers) δ: 6.85-6.70 (m, 3H),5.60-5.56 (br m, 1H), 4.00-3.46 (c, 12H), 1.17-1.13 (dd, 3H), 0.79-0.76(d and d, 3H). LRMS (Electrospray, positive): Da/e 338.1 (m+1).

EXAMPLE 240

R¹=CH₂C≡CPh; R³=COCO₂CH₃

Methyl2-{3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-oxoacetate

Prepared from Example 239 via the Mitsunobu method of Example 144 using3-phenyl-2-propyn-1-ol.

¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.41-7.26 (m, 5H), 7.07(s, 1H), 6.86-6.85 (m, 2H), 5.05-4.95 (m, 2H), 4.06-3.43 (c, 12H),0.98-0.91 (dd, 3H), 0.74-0.71 (d, 3H). LRMS (Electrospray, positive):Da/e 452.7 (m+1).

INTERMEDIATE 941-Benzyl-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-methyl-3-vinylpyrrolidine

A round bottom flask equipped with a stir bar and rubber septum wascharged with dry diethyl ether (10 mL) and methyltriphenylphosphoniumbromide (1.88 g, 5.27 mmol) under a nitrogen atmosphere. Butyllithium(2.32 mL, 5.80 mmol, 2.5 M in hexanes) then was added by syringeresulting in an orange/yellow suspension that was stirred at roomtemperature for 3 hours. A Et₂O solution of Intermediate 65 (2.0 g, 5.27mmol in 10 mL of ether) then was added, discharging the colorimmediately. After stirring at room temperature for two hours, thereaction mixture was quenched with saturated NH₄Cl solution, extractedwith EtOAc (2×50 mL), dried (Na₂SO₄), and concentrated. Columnchromatography (3Biotage system, 40M cartridge, 25% EtOAc/hexane)afforded 850 mg (43%) of an orange oil).

¹H NMR (400 MHz, CDCl₃) δ: 7.42-7.23 (m, 5H), 6.80-6.68 (m, 3H), 6.05(dd, 1H), 4.95 (dd, 1H), 4.87 (dd, 1H), 4.87 (dd, 1H), 3.86-3.79 (m,6H), 3.71 (dd, 2H), 3.22 (t, 1H), 3.04-2.96 (m, 2H), 2.81 (d, 1H), 2.52(d, 1H), 1.37-1.26 (m, 1H), 0.77 (s, 3H), 0.66-0.60 (m, 2H), 0.37-0.32(m, 2H).

INTERMEDIATE 954-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-methyl-3-vinylpyrrolidine-1-carboxylicAcid Methyl Ester

A solution of Intermediate 94 (480 mg, 1.27 mmol) in 10 mL ofacetonitrile was treated with methyl chloroformate (491 μL, 6.36 mmol),and the mixture was refluxed for 6 hours. The reaction mixture then wasconcentrated under reduced pressure, and the residue purified bychromatography (Biotage system, 40s cartridge, 10% EtOAc/hexane to 20%EtOAc/hexane) to give 237 mg of a yellow oil (54%).

¹H NMR (400 MHz, CDCl₃) δ: 6.81 (d, 1H), 6.72-6.67 (m, 2H), 5.87 (dd,1H), 5.09 (d, 1H), 4.95 (dd, 1H), 3.85 (s, 3H), 3.84-3.58 (m, 7H),3.52-3.32 (m, 2H), 3.14 (t, 1H), 1.35-1.25 (m, 1H), 0.35 (s, 3H),0.66-0.60 (m, 2H), 0.37-0.32 (m, 2H).

EXAMPLE 241

R¹=CH₂C₃H₅; R³=CO₂CH₃; R₄=H; R₅=CH₂OH; R₆=H

4-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(1,2-dihydroxyethyl)-3-methylpyrrolidine-1-carboxylicAcid Methyl Ester

A reaction vial equipped with a stir vane was charged with Intermediate95 (46 mg, 0.133 mmol), acetone (250 ul), water (500 ul), and N-methylmorpholine N-oxide (17.1 mg, 0.146 mmol). To this mixture was addedosmium tetroxide in t-butanol (50 μl, 0.004 mmol, 2.5 wt % solution).The resulting mixture was stirred at room temperature for 24 hours. Thereaction mixture then was diluted with 10% aqueous sodium thiosulfatesolution (5 mL), filtered through GF/F filter paper. The filtrate wasextracted with EtOAc (2×10 mL), dried (Na₂SO₄), and concentrated.Biotage purification (12S cartridge, 1:1:1 EtOAc/hexane/MeOH) afforded18 mg of Example 241 (36%).

¹H NMR (400 MHz, CDCl₃) δ: 6.81 (d, 1H), 3.86 (s, 3H), 3.85-3.36 (c,15H), 3.23 (dd, 1H), 1.35-1.27 (m, 1H), 0.75 (s, 3H), 0.66-0.59 (m, 2H),0.38-0.32 (m, 2H). LRMS (Electrospray, positive): Da/e 380.2 (m+1).

EXAMPLE 242

R¹=CH₂C₃H₅; R³=(S)—COCH(CH₂OC(CH₃)(CH₃)O)

[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-(2,2-dimethyl-[1,3]dioxolan-4-(S)-yl)methanone

Intermediate 67 was acylated by the Hunig's base procedure ofIntermediate 74 using 2,2-dimethyl-[1,3]dioxolane-4-(S)-carbonylchloride to afford Example 242 (22%).

¹H NMR (CDCl₃, 400 MHz) δ: 6.83-6.78, m, 4H), 4.71-4.65 (m, 1H),4.37-4.32 (m, 1H), 4.23-4.15 (m, 1H), 3.95-3.44 (m, 10H), 1.72-1.15 (m,10H), 0.76 (s, 3H), 0.67-0.62 (m, 2H), 0.38-0.33 (m, 2H). LRMS(Electrospray, positive): Da/e 434.4 (m+1).

EXAMPLE 243

R¹=CH₂C₃H₅; R³=(S)—COCH(OH)CH₂OH

1-[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-(S)-3-dihydroxypropan-1-one

Example 242 (9 mg, 20 μmol) was dissolved in a solution of aceticacid/water (3:1, 0.9 mL). The reaction mixture was stirred at roomtemperature for 72 hours. The solution was neutralized by pouring intoan NaHCO₃ solution. The solution was concentrated to dryness, then thesolids were extracted five times with CH₂Cl₂. The combined organics weredried over Na₂SO₄ and concentrated in vacuo (5.1 mg, 62%).

¹H NMR (CDCl₃, 400 MHz) δ: 6.84-6.76,m, 3H), 4.40-4.37 (m, 1H),3.89-3.32 (m, 11H), 2.33-1.95 (m, 1H), 1.34-1.12 (m, 7H), 0.89-0.81 (m,1H), 0.78-0.73 (m, 3H), 0.66-0.61 (m, 2H), 0.37-0.32 (m, 2H). LRMS(Electrospray, positive): Da/e 394.0 (m+1).

EXAMPLE 244

R¹=2-Indanyl; R³=(R)—COCH(OH)CH₂OH

(R)-2,3-Dihydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[3-(indan-2-ylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidin-1-yl}propan-1-one

Prepared from Intermediate 96 by the procedure described in Example 75and deprotected as in Example 243.

¹H NMR (CDCl₃, 300 MHz, mixture of rotomers) δ: 7.26-7.16 (m, 4H,aromatic), 6.83-6.82 (br. s, 3H, aromatic), 5.19-5.15 (m, 1H), 4.45-4.32(m, 1H), 4.10-3.50 (m, 8H), 3.80 (d, 3H, OMe), 3.45-3.12 (m, 5H),1.27-1.25 (m, 1H), 1.20-1.15 (m, 3H), 0.79-0.77 (m, 3H). LRMS(Electrospray, positive) Da/e 470.58 (m+1).

EXAMPLE 245

R¹=4-F—Ph—OCH₂CH₂CH₂; R³=(R)—COCH(OH)CH₂OH)

(S)-1-[(3S,4S)-4-{3-[3-(4-Fluorophenoxy)propoxy]-4-methoxyphenyl}-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2,3-dihydroxypropan-1-one

Prepared by the procedure set forth in Example 243. ¹H NMR (CDCl₃, 300MHz, mixture of rotomers) δ: 6.99-6.92 (m, 2H, aromatic), 6.87-6.79 (m,5H, aromatic), 4.39 (s, 1H), 4.22-4.12 (m, 4H), 4.0 (d, 1H), 3.89-3.56(m, 7H), 3.83 (s, 3H, OMe), 3.4-3.32 (dd, 1H), 2.32-2.24 (m, 2H)1.17-1.12 (m, 3H), 0.74 (d, 3H). LRMS (Electrospray, positive): Da/e492.25 (m+1).

INTERMEDIATE 961-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-[(3S,4S)-3-((R)-1-hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidin-1-yl)methanone

A round bottom flask equipped with a stir bar and rubber septum wascharged with5-[4-(1-hydroxyethyl)-4-methylpyrrolidin-3-yl)-2-methoxyphenol (2.4 g,9.55 mmol), dry CH₂Cl₂ (50 mls), and DIEA (3.49 mls, 20.1 mmol) under anitrogen atmosphere. The mixture was chilled to 0° C. and(S)-2.2-dimethyl-[1,3]dioxolane-4-carbonyl chloride (3.14 g, 19.1 mmol)in 15 ml of CH₂Cl₂ was added dropwise by syringe. The reaction mixturewas allowed to gradually warm to room temperature over a 16-hour period.The mixture then was diluted with 50 ml of CH₂Cl₂, washed with 1N HCl(2×50 ml), saturated aqueous NaHCO₃ (1×50 ml), dried over Na₂SO₄, andconcentrated to 3.9 g of a tan foam. The material was taken up in 100 mlCH₃OH and chilled to 0° C. Three equivalents of aqueous 1N LiOH thenwere added (29 ml, 29.0 mmol), the mixture was stirred at 0° C. for 2hours, then warmed to room temperature for 2 hours. The reaction mixturenext was concentrated under reduced pressure with the bath temperatureat 30° C. to remove CH₃OH. The remaining aqueous material wasneutralized with saturated NH₄Cl to pH 7 and extracted with EtOAc (2×100ml). The extracts were dried over Na2SO₄, and concentrated to 2.74 g ofa tan foam (76%).

¹H NMR (CDCl₃, 400 MHz, mixture of rotomers) δ: 6.90-6.70 (m, 3H), 5.66(br, s, 1H), 4.68 (t, 1H), 4.34 (t, 1H), 4.23-4.09 (m, 6H), 3.89 (s,3H), 3.94-3.42 (m, 5H), 1.49-1.37 (m, 6H), 1.17 (d, 3H), 0.76 (s, 3H).LRMS (Electrospray, positive): Da/e 378.3 (m−1).

EXAMPLE 246

R¹=F₃C—Ph—C≡CCH₂; R³=CO-2,2-dimethyl-1,3-dioxolan-4-yl

1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[3-(4-trifluoromethylphenyl)prop-2-ynyloxy]phenyl}-3-methylpyrrolidin-1-yl)methanone

To a flask containing anhydrous Cs₂CO₃ (67 mg, 0.206 mmol, 1.1 eq) undera nitrogen blanket was added a solution of Intermediate 96 (71 mg, 0.187mmol, 1.0 eq) in anhydrous acetone (1 mL). Intermediate 92 (52.1 mg,0.187 mmol, 1.0 eq) was added to the mixture via syringe. The reactionmixture then was heated and stirred at 65° C, for 4 hours. The reactionmixture was cooled to room temperature and diluted with water (50 mL).The aqueous solution was extracted with EtOAc (3×30 mL), and thecombined organics were washed with brine (50 mL), then dried overNa₂SO₄, filtered, and concentrated in vacuo to yield a white foamyproduct (104 g).

¹H NMR (CDCl₃, 300 MHz, mixture of rotomers) δ: 7.5-7.35 (m, 4H,aromatic), 6.96 (d, 1H, aromatic), 6.85-6.75 (m, 2H, aromatic), 4.92 (d,2H, CH₂), 4.65-4.50 (m, 1H), 4.35-4.20 (m, 1H), 4.15-4.00 (m, 1H),3.85-3.40(m, 5H), 3.8 (d, 3H, OMe), 3.35-3.30 (dd, 1H), 1.45-1.25 (2d,6H, Me), 1.0-0.9(m, 3H), 0.63 (d, 3H). LRMS (Electrospray, positive):Da/e 562.25 (m+1).

EXAMPLE 247

R¹=F₃C—Ph—C≡CCH₂; R³=CO—CH(OH)CH₂OH

(R)-2,3-Dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[3-(4-trifluoromethylphenyl)prop-2-ynyloxy]phenyl}-3-methylpyrrolidin-1-yl)propan-1-one

To a reaction vial containing Example 246 (104 mg, 0.185 mmol) was addedacetic acid (3.0 mL) and water (1.0 mL). The vial then was sealed,heated to 50° C., and stirred for 2 hours. The reaction mixture wasconcentrated in vacuo and purified by reversed-phase HPLC on a C18column (Luna 10:, C18, 250×10 mm). Gradient elution of 50-100%acetonitrile-water (0.05% TFA) yielded product as amber oil (27.8 mg,28.5% yield).

¹H NMR (CDCl₃, 300 MHz, mixture of rotomers) δ: 7.6-7.45 (m, 4H,aromatic), 7.69 (d, 1H, aromatic), 6.9-6.82 (m, 2H, aromatic), 5.0 (m,2H), 4.4-4.32 (m, 1H), 4.1-3.2 (m, 7H), 3.89 (d, 3H, OMe), 1.05 (s, 3H),0.72 (m, 3H). LRMS (Electrospray, positive): Da/e 522.15 (m+1).

EXAMPLE 248

R¹=3-thienyl-CH₂CH₂; R³=COCH₂OCH₂Ph

2-Benzyloxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(2-thiophen-3-yl-ethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

Prepared by alkylation of Example 143 by the K₂CO₃ procedure of Example7 using 2-(3-thienyl)ethyl bromide.

¹H NMR data δ: 7.27-7.38 (m, 6H); 7.05-7.07 (m, 1H); 7.12-7.13 (m, 1H);6.74-6.84 (m, 3H); 6.05 (s, 2H); 4.15-4.22 (m, 4H); 3.44-3.93 (m, 6.5H);3.86 (s, 3H); 3.14-3.24 (m, 2.5H); 1.13 (dd, 3H); 0.72 (s, 3H).

EXAMPLE 249

R¹=Ph(cyclo-C₃H₄)CH₂, R³=COCH₂OH

2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-((R)-2-phenylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

Prepared by alkylation of Example 143 by the Mitsunobu procedure ofExample 144 using 2-phenylcyclopropanol and removal of the benzyl groupby the debenzylation procedure of Intermediate 31.

¹H NMR data δ: 7.17-7.30 (m, 5H); 6.72-6.85 (m, 3H); 4.00-4.14 (m, 2H);3.49-3.98 (m, 8.5H); 3.86 (s, 3H); 3.05 (d, 0.5H): 2.86-2.93 (m, 1H);2.51-2.60 (m, 1H); 2.27-2.34 (m, 1H); 1.02-1.05 (dd, 3H); 0.74 (sd, 3H).

EXAMPLE 250

R¹=C₅H₉CH₂CH₂CH₂; R³=COCH₂OH

1-[(3S,4S)-4-[3-(3-Cyclopentylpropoxy)-4-methoxyphenyl]-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone

Prepared from Example 143 by the Mitsunobu procedure of Example 144using 3-cyclopentylpropan-1-ol and removal of the benzyl group by thedebenzylation procedure of Intermediate 31.

¹H NMR data δ: 6.75-6.83 (m, 3H); 4.12-4.15 (m, 2H); 3.96-4.01 (m,2.5H); 3.86 (s, 3H); 3.79-3.86 (m, 1H); 3.59-3.70 (m, 4H); 3.06 (d,0.5H); 1.75-1.88 (m, 5H); 1.44-1.61 (m, 6H); 1.16 (t, 5H); 0.77 (sd,3H).

EXAMPLE 251

R¹=PhCH₂CH₂CH₂; R³=COCH₂OH

2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[(4-methoxy-3-(3-phenylpropoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

Prepared from Example 143 by the K₂CO₃ procedure of Example 7 using3-phenylpropyl chloride and removal of the benzyl group by thedebenzylation procedure by Intermediate 31.

¹H NMR data δ: 7.16-7.31 (m, 5H); 6.74-6.85 (m, 3H); 4.13-4.15 (m, 2H);3.94-4.04 (m, 2H); 3.86 (s, 3H); 3.76-3.83 (m, 1H); 3.47-3.70 (m, 4H);3.04-3.07 (m, 3H); 2.80-2.85 (t, 2H); 2.10-2.20 (quint, 2H); 1.14 (t,3H); 0.74 (s, 3H).

EXAMPLE 252

R¹=1-hydroxyindan-2-yl; R³=COCH₂OH

2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[3-(1-hydroxyindan-2-yloxy)-4-methoxyphenyl]-3-methylpyrrolidin-1-yl}ethanone

Prepared from Example 143 by the K₂CO₃ procedure of Example 7 usingindene oxide and removal of the benzyl group by the debenzylationprocedure of Intermediate 31.

¹H NMR data δ: 7.48-7.51 (m, 1H); 7.24-7.32 (m, 3H); 6.85-6.96 (m, 3H);5.11-5.14 (m, 1H); 4.84-4.89 (m, 1H); 3.98-4.15 (m, 3H); 3.84-3.86 (m,1H); 3.83 (s, 3H); 3.50-3.78 (m, 4.5H); 3.16-3.32 (m, 2H); 3.06 (d,0.5H); 1.15-1.20 (m, 3H); 0.77 (s, 3H).

EXAMPLE 253

R¹=4-CH₃OPhCH₂CH₂; R³=COCH₂OH

2-Hydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[2-(4-methoxyphenyl)ethoxy]phenyl}-3-methylpyrrolidin-1-yl)ethanone

Prepared from Example 143 by the K₂CO₃ procedure of Example 7 using1-(2-chloroethyl)-4-methoxybenzene and removal of the benzyl group bythe debenzylation procedure of Intermediate 31.

¹H NMR data δ: 7.20-7.23 (d, 2H); 6.74-6.88 (m, 5H); 4.10-4.18 (m, 4H);3.72-3.91 (m, 2H); 3.86 (s, 3H); 3.80 (s, 3H); 3.48-3.64 (m, 4H);3.02-3.11 (m, 2H); 1.12-1.17 (m, 3H); 0.74 (s, 3H)

EXAMPLE 254

R¹=CH₃ (cyclo-C₃H₄) CH₂; R³=COCH₂OH2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-((R)-2-methylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

Prepared from Example 143 by the K₂CO₃ procedure of Example 7 using1-(2-chloroethyl)-4-methoxybenzene and removal of the benzyl group bythe debenzylation procedure of Intermediate 31.

¹H NMR data δ: 6.77-6.84 (m, 3H); 4.15-4.18 (m, 2H); 3.78-3.99 (m, 4H);3.86 (s, 3H); 3.49-3.71 (m, 3.5H); 3.08 (d, 0.5H); 1.14-1.19 (m, 3H);1.07 (sd, 3H); 0.92-1.03 (m, 1H); 0.76-0.77 (m, 4H); 0.50-0.52 (m, 1H);0.37-0.41 (m, 1H).

EXAMPLE 2551-(R)-[1-(2-Benzyloxyethyl)-4-(S)-(3-cyclopentyloxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]-ethanol

Intermediate 68 (86.4 mg, 0.27 mmol) was dissolved in 1,2-dichloroethane(1 mL) and the solution was treated with benzyloxyacetaldehyde (38 μL,0.27 mmol), followed by sodium triacetoxyborohydride (81 mg, 0.38 mmol).The reaction was stirred for 18 hours at room temperature. Additionalsodium triacetoxyborohydride (40 mg, 0.19 mmol) was added and stirringcontinued for 8 hours. The reaction mixture was diluted with 1.0 M NaOH(0.5 mL) and stirred vigorously for 15 minutes. The layers wereseparated, the aqueous phase was washed with CH₂Cl₂, and the organiclayers were combined. After washing with 6% NaHCO₃, the organics weredried with Na₂SO₄, then concentrated in vacuo. The crude material (129mg) was chromatographed on silica gel with CHCl₃/95% ethanol/conc. NH₄OH(170 : 15 : 1), providing Example 255 (27 mg, 22%).

¹H NMR (CDCl₃, 400 MHz) δ: 7.36-7.25 (m, 5H), 6.81-6.73 (m, 3H),4.79-4.73 (m, 1H), 4.54 (s, 1H), 3.82 (s, 3H), 3.71-3.54 (m, 4H),3.40-3.35 (m, 1H), 3.24-3.21 (m, 1H), 2.80-2.67 (m, 2H), 2.63-2.56 (m,1H) 2.16-2.09 (m, 1H), 1.95-1.88 (m, 8H), 1.65-1.57 (m, 2H), 1.22-1.10(m, 3H), 0.49 (m, 3H). LRMS (Electrospray, positive): 454.5 Da/e (m+1).

EXAMPLE 2561-(R)-[4-(S)-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-hydroxyethyl)-3-(S)-methylpyrrolidin-3-yl]ethanol

Example 255 (25 mg, 55 mmol) was subjected to the debenzylationprocedure of Intermediate 31 to afford Example 256 (7.4 mg, 28%) as theTFA salt after HPLC purification.

¹H NMR (CDCl₃, 400 MHz) δ: 6.84-6.65 (m, 3H), 5.40-4.90 (brd, 2H), 4.74(brd s, 1H), 4.26-3.21 (m, 11H), 1.97-1.73 (m, 6H), 1.66-1.56 (m, 3H),1.33-0.77 (m, 4H), 0.69 (s, 3H). LRMS (Electrospray, positive): 364.4Da/e (m+1)

EXAMPLE 2572-Benzyloxy-1-[4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-hydroxymethyl-3-methylpyrroli-din-1-yl]ethanone

[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]methanol(100 mg, 0.34 mmol) was dissolved in CH₂Cl₂ (1.7 mL), and the solutionwas cooled to 0° C. DIEA (144 μL, 0.82 mmol) was added, followed bybenzyloxyacetyl chloride (114 μL, 0.72 mmol). The reaction was allowedto warm to room temperature slowly and stirred for 18 hours. Water wasadded (0.25 mL) and the reaction was stirred for 1.5 hours. CH₂Cl₂ wasadded and the mixture was washed once with water, twice with iN HCl,once with water, twice with 6% NaHCO₃, then dried over Na₂SO₄ andconcentrated in vacuo. The residue was dissolved in THF (1 mL) andcooled to 0° C. A solution of LiOH in water (1.36M, 1 mL, 1.36 mmol) wasadded and the hydrolysis was allowed to proceed at 0° C. for 4 hours.The reaction mixture was quenched with saturated NH₄Cl, and the THF wasremoved by concentrated in vacuo. The residue 6% NaHCO₁, dried overNa₂SO₄ and concentrated in vacuo.

¹H NMR (CDCl₃, 400 MHz) δ: 7.40-7.28 (m, 5H), 6.83-6.79 (m, 1H),6.73-6.66 (m, 2H), 4.66 (s, 2H), 4.16-4.13 (m, 2H), 3.86 (s, 3H),3.83-3.78 (m, 3H), 3.63-3.26 (brd m, 4H), 3.06-3.00 (m, 1H), 2.50-2.45(brd m, 1H), 1.34-1.12 (m, 1H), 1.03-0.99 (m, 2H), 0.73 (s, 3H),0.66-0.61 (m, 2H), 0.36-0.32 (m, 2H) LRMS (Electrospray, positive): Da/e440.3 (m+1).

INTERMEDIATE 97[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]methanol

Intermediate 65 (0.99 g, 2.6 mmol) was dissolved in ethanol (95%, 10 mL)and the solution was treated with Pearlman's catalyst (20% Pd(OH)₂ oncarbon, 250 mg). The mixture was hydrogenated at 1 atmosphere of H2 for16 hours. Additional catalyst (250 mg) was added and the reactioncontinued for an additional 24 hours. The catalyst was removed byfiltration and the reaction mixture was concentrated in vacuo (0.68 g,899%).

¹H NMR (CDCl₃, 400 MHz) δ: 6.84-6.73 (m, 3H), 3.87-3.83 (m, 4H),3.59-3.47 (m, 3H), 3.30-3.20 (m, 3H), 2.85 (d, J=10.6, 1H), 2.35-2.12(brd m, 1H), 1.35-1.27 (m, 1H), 0.64-0.60 (m, 4H), 0.37-0.31 (m, 2H),0.36-0.32 (m, 2H). LRMS (Electrospray, positive): Da/e 377.3 (m+1).

EXAMPLE 2581-(2-Benzyloxyacetyl)-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidine-3-carbalde-hyde

oxalyl chloride (2.0 M in CH₂Cl₂₁, 0.175 mL, 0.35 mmol) was added toCH₂Cl₂ (0.52 mL). The resulting solution was cooled to −60° C. Asolution of DMSO (47 mL, 0.66 mmol) dissolved in CH₂Cl₂ (0.18 mL) thenwas added dropwise. The solution was stirred for 5 minutes and Example257 (dissolved in 1.0 mL CH₂Cl₂) added to a Swern oxidation mixture.After the reaction had been stirred for 30 minutes at −60° C, Et₃N (0.25mL) was added and the reaction mixture was warmed to room temperature.After 30 minutes, water was added and the solution was stirredvigorously for 15 minutes. The layers were separated, the aqueous phasewashed once with CH₂Cl₂. The combined organic layers were washed withsaturated NaCl, dried over Na₂SO₄, and concentrated in vacuo. The crudematerial was chromatographed on SiO₂ using EtOAc/hexanes (2:1), (76 mg,50%).

¹H NMR (CDCl₃, 400 MHz) δ: 9.62-9.57 (m, 1H), 7.41-7.30 (m, 5H),6.84-6.78 (m, 1H), 6.68-6.56 (m, 2H), 4.68-4.63 (m, 2H), 4.20-4.10 (m,2H), 4.05-3.32 (m, 5H), 3.87 (s, 3H), 1.57-1.55 (m, 2H), 1.33-1.24 (m,1H), 0.92-0.88 (m, 3H), 0.67-0.60 (m, 2H), 0.37-0.31 (m, 2H).

EXAMPLE 2591-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-[(3S,4S)-3-((R)-1-hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidin-1-yl]methanone

To a stirred solution of Intermediate 70 (73.5 mg, 0.293 mmol, 1.0 eq)in CH₂C1₂ (3 mL) at room temperature under a nitrogen blanket was addedEt₃N (65.2 mg, 0.645 mmol), followed by2,2-dimethyl-1,3-dioxolane-(4R)-carbonyl chloride (53.2 mg, 0.322 mmol).The reaction was stirred at room temperature overnight. The reactionmixture then was poured into 50 mL EtOACt washed with brine, dried withNa₂S₄, and concentrated in vacuo to give a foamy product (94 mg, 85%yield). The crude product was hydrolyzed by LiOH via Intermediate 5 toyield Example 259.

¹H NMR (CDCl₃, 300 MHz) δ: 6.97-6.58 (m, 3H, aromatic), 4.68 (t, 1H,J=6.4 Hz), 4.44-4.34 (m, 1H), 4.24-3.95 (m, 1H), 3.94-3.50 (m, 5H), 3.87(d, 3H, OMe), 3.42 (d, 1H, J=12.4Hz), 3.35 (d, 1H, J=12.4Hz), 1.4 (m,6H), 1.15 (m, 3H), 0.75 (m, 3H)

EXAMPLE 2601-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}methanone

Prepared from Example 259 (126 mg, 0.332 mmol, 1.0 eq) and Intermediate90 (69.8 mg, 0.332 mmol, 1.0 eq) by the method of Example 176 to yield awhite foamy product (160 mg).

¹H NMR (CDCl₁, 300 MHz, mixture of rotamers) δ: 7.42-7.25 (m, 5H,aromatic), 7.08 (d, 1H, aromatic), 6.86 (d, 2H, aromatic), 5.0 (d, 2H,CH₂), 4.72-4.60 (m, 1H), 4.45-4.32 (m, 1H), 4.22-4.10 (m, 1H), 3.95-3.70(m, 3H), 3.89 (s, 3H, OMe), 3.70-3.45 (m, 2H), 3.44-3.29 (m, 1H),1.5-1.38 (2d, 6H, Me), 1.02-0.75-0.65 (m, 3H), 0.63 (d, 3H). LRMS(Electropray, positive): Da/e 494.55 (m+l1).

EXAMPLE 261(R)-2,3-Dihydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}propan-1-one

To a reaction vial containing Example 260 (160 mg, 0.323 mmol) was addedacetic acid (3.0 mL) and water (1.0 mL). The vial was sealed, heated to50° C., and stirred for 2 hours. The reaction was concentrated in vacuoand purified by reversed-phase HPLC on a C18 column (Luna 10 μ, C18,250×10 mm). Gradient elution of 50-100% acetonitrile-water (0.05% TFA)provided Example 261 as white foamy solid (52.2 mg, 35.6% yield).

¹H NMR (CDC₃₁, 300 MHz, mixture of rotamers) δ: 7.5-7.21 (m, 5H,aromatic), 7.05 (m, 1H, aromatic), 6.9-6.75 (m, 2H, aromatic), 5.0 (d,2H), 4.31 (s, 1H), 4.01-3.2 (m, 9H), 3.88 (s, 3H, OMe), 1.01-0.9 (m,3H), 0.7 (s, 3H). LRMS (Electrospray, positive): Da/e 454.20 (m+1).

EXAMPLE 2621-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-[(3S,4S)-3-((R)-1-hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidin-1-yl]methanone

To a stirred solution of Intermediate 70 (73.5 mg, 0.293 mmol, 1.0 eq)in CH₂Cl₂ (3 mL) at room temperature under a nitrogen blanket was addedEt₃N (65.2 mg, 0.645 mmol), followed by2,2-dimethyl-1,3-dioxolane-(4S)-carbonyl chloride (53.2 mg, 0.322 mmol).The reaction was stirred at room temperature overnight, then poured into50 mL EtoAc, washed with brine, dried with Na₂SO₄, and concentrated invacuo to give a foamy product (94 mg, 85% yield). The crude product washydrolyzed by LiOH via Intermediate 5 to yield Example 262.

¹H NMR (CDCl₃, 300 MHz) δ: 6.93-6.65 (m, 3H, aromatic), 5.68 (s, 1H),4.67 (m, 1H), 4.34 (m, 1H), 4.21 (m, 1H), 3.94-3.40 (m, 5H), 3.89 (s,3H, OMe), 1.4 (m, 6H), 1.16 (m, 3H), 0.76 (m, 3H).

EXAMPLE 2631-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}methanone

Prepared from Example 262 (126 mg, 0.332 mmol, 1.0 eq) and Intermediate90 (69.8 mg, 0.332 mmol, 1.0 eq) by the method of Example 176 to yield awhite foamy product (160 mg,).

¹H NMR (CDCl₃, 300 MHz, mixture of rotamers) δ: 7.52-7.15 (m, 5H,aromatic), 7.08 (d, 1H, aromatic), 6.86 (d, 2H, aromatic), 5.98 (m, 2H,CH₂), 4.64 (m, 1H), 4.35-4.32 (m, 1H), 4.22-4.10 (m, 1H), 3.97-3.36 (m,5H), 3.89 (s, 3H, OMe), 1.5-1.38 (2d, 6H, Me), 1.02-0.75 (m, 3H), 0.74(s, 3H). LRMS (Electrospray, positive): Da/e 494.55 (m+1).

EXAMPLE 264(S)-2,3-Dihydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}propan-1-one

To a reaction vial containing Example 263 (160 mg, 0.323 mmol) was addedacetic acid (3.0 mL) and water (1.0 mL). The vial was sealed, heated to50° C. and stirred for 2 hours. The reaction was concentrated in vacuoand purified by reversed-phase HPLC on a C18 column (Luna 10μ, C18,250×1O mm). Gradient elution of 50-100% acetonitrile-water (0.05% TFA)gave product as white foamy solid (52.2 mg, 35.6% yield).

¹H NMR (CDC1₃, 300 MHz, mixture of rotamers) δ: 7.44-7.18 (m, 5H,aromatic), 7.08 (s, 1H, aromatic), 6.86 (s, 2H, aromatic), 4.6 (s, 2H,CH₂), 4.4-4.3 (m, 1H), 4.01-4.62 (m, 7H), 3.89 (s, 3H, OMe), 3.59-3.46(m, 1H), 3.32-3.29 (m, 1H), 2.4 (m, 1H), 0.95 (m, 3H), 0.72 (d, 3H).LRMS (Electrospray, positive): Da/e 454.20 (m+1). [α]_(D)=14.6° (c=1.00,EtOH)

EXAMPLE 265

R₁=t-Bu; R₃=(S)—COCH(OAc)CH₂Ph

Prepared from Intermediate 73 by acylation with acetic acid(S)-1-chlorocarbonyl-2-phenylethyl ester according to procedure of F.Babudri et al., Tetrahedron, 8, 2431-2440 (1999).

LRMS (Electrospray, positive): m/z 498 (m+1).

EXAMPLE 266

R₁=H; R₃=(S)—COCH(OAc)CH₂Ph

Prepared from Example 265 by the TFA method of Example 143 to affordExample 266. LRMS (Electrospray, positive): m/z 442 (m+1).

EXAMPLE 267 Acetic Acid(S)-1-Benzyl-2-{(3S,4S)-3-((R)-1-hydroxy-ethyl)-4-(4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}-2-oxo-ethylEster

R₁=PhC≡CCH₂; R₃=(S)—COCH(OAc)CH₂Ph

Example 266 (88 mg, 0.2 mmol) and Intermediate 90 (50 mg, 0.24 mmol)were subjected to the Cs₂CO₃ procedure of Example 176, and the cruderesidue (110 mg) was used without further purification.

EXAMPLE 268(S)-2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}-3-phenylpropan-1-one

R₁=PhC≡CCH₂; R₃=(S)—COCH(OH)CH₂Ph

Example 267 (110 mg crude, 0.2 mmol theoretical) was subjected to theO-Acetate deprotection procedure and purified by HPLC (20×50 mm YMCCombiPrep C18 column, 20 mL/min, 10-95% acetonitrile/water in 7 min) toyield Example 268 (38 mg, 75%).

¹H NMR (300 MHz, CDCl₃, mixture of rotamers) δ: 7.50-7.16 (m, 10H),7.10-6.52 (m, 3H), 5.05-4.92 (m, 2H), 4.52-4.36 (m, 1H), 3.88 (s, 3H),3.87-2.72 (m, 9H), 1.48/1.29 (2d, J=4.3/4.6 Hz, 1H), 0.93/0.88 (2d,J=6.4 Hz, 3H), 0.66/0.51 (2s, 3H). LRMS (Electrospray, positive): m/e514 (m+H)⁺.

The compounds of structural formula (II) were tested for an ability toinhibit PDE4. The ability of a compound to inhibit PDE4 activity isrelated to the IC₅₀ value for the compound, i.e., the concentration ofinhibitor required for 50% inhibition of enzyme activity. The IC₅₀ valuefor compounds of structural formula (II) were determined usingrecombinant human PDE4.

The in vitro phosphodiesterase activity inhibitory IC₅₀ values, and theresulting calculated K_(i) values of compounds set forth in the exampleswere determined by measuring the inhibition of cAMP hydrolysis as afunction of the concentration of the test compound over the range of 0to 1 mM. The K_(i) values of the compounds tested in the aforementionedassay ranged from about 0.0003 μM to about 100 μM.

The compounds of the present invention typically exhibit an IC₅₀ valueagainst recombinant human PDE4 of less than about 50 μM, and preferablyless than about 25 μM, and more preferably less than about 15 μm. Thecompounds of the present invention typically exhibit an IC₅₀ valueagainst recombinant human PDE4 of less than about 1 μM, and often lessthan about 0.05 μM. To achieve the full advantage of the presentinvention, a present PDE4 inhibitor has an IC₅₀ of about 700 pM(picomolar) to about 15 μM.

The IC₅₀ values for the compounds were determined fromconcentration-response curves typically using concentrations rangingfrom 0.1 pM to 500 μM. Tests against other PDE enzymes using standardmethodology, as described in Loughney et al., J. Biol. Chem., 271, pp.796-806 (1996), also showed that compounds of the present invention arehighly selective for the cAMP-specific PDE4 enzyme.

In particular, a compound of the present invention, i.e., Sample 66, hasan IC₅₀ vs. human recombinant PDE4B of 0.015 μM, but has an IC₅₀ vs.PDE1A of 80 μM, vs. PDE1B of 100 μM, vs. PDElC of 12 μM, vs. PDE2 of 450μM, vs. PDE3A of 40 μM, vs. PDE5 of 270 μM, and vs. PDE7 of 36 μM. Thisillustrates the selectivity of the present compound with respect toinhibiting PDE4.

The compounds of structural formula (II) also were tested for an abilityto reduce TNFα secretion in human peripheral blood lymphocytes. Theability to reduce TNFα secretion is related to the EC₅₀ values (i.e.,the effective concentration of the compound capable of inhibiting 50% ofthe total TNFα).

The in situ inhibition of TNFα release derived from endotoxin treatedisolated human peripheral blood lymphocytes resulted in EC₅₀ values ofcompounds set forth in the examples were determined as a function of theconcentration of the test compound over a range of 0 to 100 μM. The EC₅₀values of the compounds tested in the aofrementioned assay ranged fromabout 0.0002 μM to about 20 μM.

The compounds of the present invention typically exhibit an EC, value ofless than about 50 μM, and preferably less than about 25 μM, and morepreferably less than about 15 μM. The compounds of the present inventiontypically exhibit a PBL/TNFα EC₅₀ value of less than about 1 μM, andoften less than about 0.05 μM. To achieve the full advantage of thepresent invention, a present PDE4 inhibitor has an EC₅₀ value of about1000 pM (picomolar) to about 20 μM.

The production of recombinant human PDEs and the IC₅₀ and EC₅₀determinations can be accomplished by well-known methods in the art.Exemplary methods are described as follows:

EXPRESSION OF HUMAN PDEs Expression in Baculovirus-Infected Spodopterafugiperda (Sf9) Cells

Baculovirus transfer plasmids were constructed using either pBlueBacIII(Invitrogen) or pFastBac (BRL-Gibco). The structure of all plasmids wasverified by sequencing across the vector junctions and by fullysequencing all regions generated by PCR. Plasmid pBB-PDE2A3/6 containedthe complete open reading frame of PDE1A3 (Loughney et al., J. Biol.Chem., 271, pp. 796-806 (1996)) in pBlue-BacIII. Plasmid Hcam3aBBcontained the complete open reading frame of PDE1C3 (Loughney et al.(1996)) in pBlueBacIII. Plasmid pBB-PDE3A contained the complete openreading frame of PDE3A (Meacci et al., Proc. Natl. Acad. Sci., USA, 89,pp. 3721-3725 (1992)) in pBlueBacIII.

Recombinant virus stocks were produced using either the MaxBac system(Invitrogen) or the FastBac system (Gibco-BRL) according to themanufacturer's protocols. In both cases, expression of recombinant humanPDEs in the resultant viruses was driven off the viral polyhedronpromoter. When using the MaxBac® system, virus was plaque purified twicein order to insure that no wild type (occ+) virus contaminated thepreparation. Protein expression was carried out as follows. Sf9 cellswere grown at 27° C. in Grace's Insect culture medium (Gibco-BRL)supplemented with 10% fetal bovine serum, 0.33% TC yeastolate, 0.33%lactalbumin hydrolysate, 4.2 mM NaHCO₃, 10 μg/mL gentamycin, 100unitg/mL penicillin, and 100 μg/mL streptomycin. Exponentially growingcells were infected at a multiplicity of approximately 2 to 3 virusparticles per cell and incubated for 48 hours. Cells were collected bycentrifugation, washed with nonsupplemented Grace's medium, andquick-frozen for storage.

Expression in Saccharomyces cerevisiae (Yeast)

Recombinant production of human PDE1B, PDE2, PDE4A, PDE4B, PDE4C, PDE4D,PDE5, and PDE7 was carried out similarly to that described in Example 7of U.S. Pat. No. 5,702,936, incorporated herein by reference, exceptthat the yeast transformation vector employed, which is derived from thebasic ADH2 plasmid described in Price et al., Methods in Enzymology,185, pp. 308-318 (1990), incorporated yeast ADH2 promoter and terminatorsequences and the Saccharomyces cerevisiae host was theprotease-deficient strain BJ2-54 deposited on Aug. 31, 1998 with theAmerican Type Culture Collection, Manassas, Virginia, under accessionnumber ATCC 74465. Transformed host cells were grown in 2×SC-leu medium,pH 6.2, with trace metals, and vitamins. After 24 hours, YEPmedium-containing glycerol was added to a final concentration of 2XYET/3% glycerol. Approximately 24 hr later, cells were harvested,washed, and stored at −70° C.

CALMODULIN PURIFICATION

Calmodulin used for activation of the PDE1 enzymes was purified frombovine testes essentially as described by Dedman et al., Methods inEnzymology, 102, pp. 1-8 (1983) using the Pharmacia Phenyl-Sepharose®procedure.

IMMOBILIZATION OF CALMODULIN ON AGAROSE

Calmodulin was immobilized on BioRad AffiGels® 15 per manufacturer'sinstructions.

HUMAN PHOSPHODIESTERASE PREPARATIONS Phosphodiesterase ActivityDeterminations

Phosphodiesterase activity of the preparations was determined asfollows. PDE assays utilizing a charcoal separation technique wereperformed essentially as described in Loughney et al. (1996). In thisassay, PDE activity converts [32P]cAMP or [32P]cGMP to the corresponding[32P]5′-AMP or [32P]5′-GMP in proportion to the amount of PDE activitypresent. The [32P]5′-AMP or [32P]5′-GMP then was quantitativelyconverted to free [32P]phosphate and unlabeled adenosine or guanosine bythe action of snake venom 5′-nucleotidase. Hence, the amount of[32P]phosphate liberated is proportional to enzyme activity. The assayiwas performed at 30° C. in a 100 μL reaction mixture containing (finalconcentrations) 40 mM Tris HCl (pH 8.0), 1 μM ZnSO₄, 5 mM MgCl₂, and 0.1mg/mL bovine serum albumin (BSA). Alternatively, in assays assessingPDE1-specific activity, incubation mixtures further incorporated the useof 0.1 mM CaCl₂ and 10 μg/mL calmodulin. PDE enzyme was present inquantities that yield <30% total hydrolysis of substrate (linear assayconditions). The assay was initiated by addition of substrate (1 mM[32P]cAMP or cGMP), and the mixture was incubated for 12 minutes.Seventy-five (75) μg of Crotalus atrox venom then was added, and theincubation was continued for 3 minutes (15 minutes total). The reactionwas stopped by addition of 200 μL of activated charcoal (25 mg/mLsuspension in 0.1 M NaH₂PO₄, pH 4). After centrifugation (750×g for 3minutes) to sediment the charcoal, a sample of the supernatant was takenfor radioactivity determination in a scintillation counter and the PDEactivity was calculated.

Inhibitor analyses were performed similarly to the method described inLoughney et al., J. Biol. Chem., 271, pp. 796-806 (1996), except bothcGMP and cAMP were used, and substrate concentrations were kept below 32nM, which is far below the Km of the tested PDEs.

Purification of PDE1A3 from SF9 Cells

Cell pellets (5 g) were mixed with 10 mL of Lysis Buffer (50 mM MOPS pH7.5, 2 mM dithiothreitol (DTT), 2 mM benzamidine HCl, 5 μM ZnSO₄, 0.1 mMCaCl₂, 20 μg/mL calpain inhibitors I and II, and 5 μg/mL each ofleupeptin, pepstatin, and aprotinin) at room temperature. The cells werelysed by passage through a French pressure cell (SLM-Aminco®, SpectronicInstruments, Inc., Rochester N.Y.). The resultant lysate was centrifugedin a Beckman ultracentrifuge using a type T180 rotor at 45,000 rpm for 1hr. The supernatant was recovered and filtered through a 0.2 μm filter.This filtrate was applied to a 2.6×90 cm column of SEPHACRYL® S-300equilibrated in Column Buffer A (Lysis Buffer containing 100 mM NaCl,and 2 mM MgCl₂). The column flow rate was adjusted to 1 mL/min andfractions of 7 mL were collected. Active fractions were pooled andsupplemented with 0.16 mg of calmodulin. The enzyme was appliedovernight at a flow rate of 0.2 mL/min to an ACC-1 agaroseimmunoaffinity column as described in Hansen et al., Methods inEnzymology 159, pp. 453-557 (1988). The column was washed with 5 volumesof Column Buffer B (Column Buffer A with-out NaCl) and followed by 5volumes of Column Buffer C (Column Buffer A containing 250 mM NaCl). Thecolumn was eluted with Column Buffer D (50 mM MOPS pH 7.5, 1 mM EDTA, 1mM EGTA, 1 mM DTT, 1 mM benzamidine HCl, 100 mM NaCl, 20 μg/mL calpaininhibitors I and II, and 5 μg/mL each of leupeptin, pepstatin, andaprotinin) by applying one column volume at 0.1 mL/min, stopping flowfor 1 hour, and then continuing elution at the same flow rate. Fractionsof 0.5 mL were collected. Fractions displaying activity were pooled, andfirst dialyzed against dialysis buffer containing 25 mM MOPS pH 7.5, 100mM NaCl, 10 μM ZnSO₄, 1 mM CaCl₂, 1 mM DTT, and 1 mM benzamidine HCl. Asubsequent dialysis against dialysis buffer containing 50% glycerol wasperformed prior to quick-freezing the sample with dry ice and storage at−70° C. The resultant preparations were about 10 to 15% pure bySDS-PAGE. These preparations had specific activities of about 5 to 20μmol cAMP hydrolyzed per minute per milligram protein.

Purification of PDE1B from S. cerevisiae

Yeast cells (50 g) were thawed by mixing with 100 mL glass beads (0.5mM, acid washed) and 200 mL Buffer A at room temperature. Buffer Aconsisted of 50 mM MOPS pH 7.5, 1 mM DTT, 2 mM benzamidine HCl, 0.01 mMZnSO₄, 5 mM MgCl₂, 20 μg/mL calpain inhibitors I and II, and 5 μg/mLeach of leupeptin, pepstatin, and aprotinin. The mixture was cooled to4° C., transferred to a Bead-Beater®, and the cells lysed by rapidmixing for 6 cycles of 30 seconds each. The homogenate was centrifugedfor 15 minutes in a Beckman J2-21M centrifuge using a JA-10 rotor at9,000 rpm and 4° C. The supernatant was recovered and centrifuged in aBeckman XL-80 ultracentrifuge using a TI45 rotor at 36,000 rpm for 45minutes at 4° C. The supernatant was recovered and PDE1B wasprecipitated by the addition of solid ammonium sulfate (0.33 g/mLsupernatant) while stirring in an ice bath and maintaining the pHbetween 7.0 and 7.5. This mixture then was centrifuged for 22 minutes ina Beckman J2 centrifuge using a JA-10 rotor at 9,000 rpm (12,000×g). Thesupernatant was discarded and the pellet was dissolved in 100 mL ofbuffer B (50 mM MOPS pH 7.5, 1 mM DTT, 1 mM benzamidine HCl, 0.01 mMZnSO₄, 2 rnM MgCl₂, 2 mM CaCl₂, and 5 μg/mL each of leupepcin,pepstatin, and aprotinin). The pH and conductivity were corrected to 7.5and 15-20 milli-Siemens (mS), respectively. This solution was loadedonto a 20 mL column of calmodulin-Agarose that had been equilibratedwith 10 column volumes of Buffer B at a rate of 1 mL/min. Theflow-through was reapplied to the column at least 5 times. The columnwas washed with 5 volumes of Buffer B, 5 volumes of buffer B containing250 mM NaCl, and 2 volumes of Buffer B without NaCl again. Elution wasaccomplished by applying one volume of Buffer C (50 mM MOPS pH 7.5, 1 mMEDTA, 1 mM EGTA, 1 mM DTT, 1 mM benzamidine HCl) at 0.33 mL/min, thenstopping flow for 1 hour before continuing the elution. Fractions ofabout 4 mL were collected and assayed for PDE activity. Active fractionswere pooled and concentrated to a volume of 5 mL, using an Amiconultrafiltration system. The concentrate was then applied to a 320 mLSephacryl® S-300 column (1.6×150 cm) that had been equilibrated with atleast 2 volumes of Buffer D (25 mM MOPS pH 7.5, 1 mM DTT, 1 mMbenzamidine HCl, 0.01 mM ZnSO₄, 2 mM CaCl₂, and 100 mM NaCl). The columnwas developed at a flow rate of 1 mL/min (11 cm/hr), and 5 mL fractionswere collected. The activity peak was pooled and dialyzed overnightagainst Buffer D containing 50% glycerol. The purified enzyme was frozenon dry ice and stored at −70° C. The resultant preparations wereabout >90% pure by SDS-PAGE. These preparations had specific activitiesof about 10 to 30 μmol cGMP hydrolyzed per minute per milligram protein.

Purification of PDE1C3 from Sf9 Cells

Cell pellets (5 g) were thawed on ice with 20 mL of Lysis Buffer (50 mMMOPS pH 7.4, 10 μM ZnSO₄, 0.1 mM CaCl₃, 1 mM DTT, 2 mM benzamidine HCl,5 μg/mL each of pepstatin, leupeptin, and aprotinin). Cells were lysedby passage through a French® pressure cell (SLM-Aminco®, SpectronicInstruments) while temperatures were maintained below 10° C. Theresultant cell homogenate was centrifuged at 36,000 rpm at 4° C. for 45min in a Beckman ultracentrifuge using a Type TI45 rotor. Thesupernatant was discarded and the resultant pellet was resuspended with40 mL of Solubilization Buffer (Lysis Buffer containing 1 M NaCl, 0.1 MMgCl₂, 1 mM CaCl₂, 20 μg/mL calmodulin, and 1% Sulfobetaine SB12 (Z3-12)by sonicating using a VibraCell tuner with a microtip for 3×30 seconds.This was performed in a crushed ice/salt mix for cooling. Followingsonication, the mixture was slowly mixed for 30 minutes at 4° C. tofinish solubilizing membrane bound proteins. This mixture wascentrifuged in a Beckman ultracentrifuge using a type TI45 rotor at36,000 rpm for 45 minutes. The supernatant was diluted with Lysis Buffercontaining 10 μg/mL calpain inhibitors I and II. The precipitatedprotein was centrifuged for 20 minutes at 9,000 rpm in a Beckman JA-10rotor. The recovered supernatant then was subjected to Mimetic Blue® APAgarose Chromatography.

To run the Mimetic Blue® AP Agarose Column, the resin initially wasshielded by the application of 10 bed volumes of 1% polyvinylpyrrolidone(i.e., MW of 40,000) to block nonspecific binding sites. The looselybound DVP-40 was removed by washing with 10 bed volumes of 2 M NaCl, and10 mM sodium citrate pH 3.4. Just prior to addition of the solubilizedPCE1C3 sample, the column was equilibrated with 5 bed volumes of ColumnBuffer A (50 mM MOPS pH 7.4, 10 μM ZnSO₄, 5 mM MgCl₂, 0.1 mM CaC₁, 1 mMDTT, 2 mM benzamidine HCl).

The solubilized sample was applied to the column at a flow rate of 2mL/min with recycling such that the total sample was applied 4 to 5times in 12 hours. After loading was completed, the column was washedwith 10 column volumes of Column Buffer A, followed by 5 column volumesof Column Buffer B (Column Buffer A containing 20 mM 5′-AMP), andfollowed by 5 column volumes of Column Buffer C (50 mM MOPS pH 7.4, 10μM ZnSO₄, 0.1 mM CaCl₂, 1 mM DTT, and 2 mM benzamidine HCl). The enzymewas eluted into three successive pools. The first pool consisted ofenzyme from a 5-bed volume wash with Column Buffer C containing 1 mMcAMP. The second pool consisted of enzyme from a 10-bed volume wash withColumn Buffer C containing 1 M NaCl. The final pool of enzyme consistedof a 5-bed volume wash with Column Buffer C containing 1 M NaCl and 20mM cAMP.

The active pools of enzyme were collected and the cyclic nucleotideremoved via conventional gel filtration chromatography or chromatographyon hydroxyapatite resins. Following removal of cyclic nucleotides, theenzyme pools were dialyzed against Dialysis Buffer containing 25 mM MOPSpH 7.4, 10 μM ZnSO₄, 500 mM NaCl, 1 mM CaCl₂, 1 mM DTT, 1 mM benzamidineHCl, followed by dialysis against Dialysis buffer containing 50%glycerol. The enzyme was quick-frozen with the aid of dry ice and storedat −70° C.

The resultant preparations were about >90% pure by SDS-PAGE. Thesepreparations had specific activities of about 0.1 to 1.0 μmol cAMPhydrolyzed per minute per milligram protein.

Purification of PDE2 from S. cerevisiae

Frozen yeast cell pellets from strain YI34 (10 g, stored at −70° C.)were allowed to thaw on ice in 25 mL of Lysis Buffer (50 mM MOPS, pH7.2, 1 mM EDTA, 1 mM EGTA, 0.1 mM DTT, 0.1 mM4-(2-amino-ethyl)benzenesulfonyl fluoride (AEBSF), 1 μg/mL of pepstatin,leupeptin, aprotinin, calpain inhibitors I and II, and 2 mMbenzamidine). Cells were lysed by three passages through a French®pressure cell (SLM-Aminco®, Spectronic Instruments). The lysate wascentrifuged at 36,000 rpm in a Beckman Ultracentrifuge rotor Type 45Tifor 60 minutes at 40° C. The supernatant was separated from sediment andpassed through a 15 mL Epoxy-cGMP Sepharos® resin at 40° C. two times atabout 0.5 mL/min. The column subsequently was washed with 45 mL of WashBuffer 1 (50 mM MOPS, pH 7.2, 0.1 mM EDTA, 0.1 mM DTT). Following thiswash, the column was washed with 45 mL of Wash Buffer 2 (Wash Buffer 1containing 0.5 M NaCl). Following this salt wash, the column was washedwith 15 mL of Wash Buffer 3 (Wash Buffer 1 containing 0.25 M NaCl). Thecolumn was transferred to room temperature and allowed to warm.Approximately 25 mL of Elution Buffer (Wash Buffer 3 containing 10 mMcGMP, maintained at room temperature) was applied to the column and theeffluent was collected in 2 mL fractions. Small aliquots of each of thefractions were diluted 20-fold in PBS containing 5 mM MgCl₂ to allowhydrolysis of the competing ligand and to aid detection of PDE2activity. Active fractions were passed through a Pharmacia PD-10® gelfiltration column to exchange into Wash Buffer 3. This exchanged poolwas diluted 50% v/v with sterile 80% glycerol and stored at −20° C. Theresultant preparations were greater than 85% pure as judged by SDS-PAGEwith subsequent staining of protein by Coomassie R-250. Thesepreparations had specific activities of about 150 to 250 μmol cGMPhydrolyzed per minute per milligram protein.

Preparation of PDE3A from Sf9 Cells

Cells (2×1010) were suspended in Lysis Buffer containing 50 mM MOPS pH7.5, 2 mM DTT, 2 mM benzamidine HCl, 5 μM ZnSO₄, 0.1 mM CaCl₂, 20 μg/mLcalpain inhibitors I and II, and 5 μg/mL each of leupeptin, pepstatin,and aprotinin. The mixture was sonicated twice for 30 seconds and thecells were lysed in a French® pressure cell (SLM-Aminco®, SpectronicInstruments) at 4° C. The lysate was centrifuged 100,000×g for 45minutes. The pellet was washed once in Lysis Buffer and suspended in 46mL Lysis Buffer with a Dounce homogenizer. Aliquots were stored at −70°C. These preparations had specific activities of about 1 to 2 nmol cAMPhydrolyzed per minute per milligram protein.

HUMAN PDE4A, 4B, 4C, 4D PREPARATIONS Preparation of PDE4A from S.cerevisiae

Yeast cells (50 9 of yeast strain YI26 harboring HDUN1.46) were thawedat room temperature by mixing with 50 mL of Lysis Buffer (50 mM MOPS pH7.5, 10 μM ZnSO₄, 2 mM MgCl₂, 14.2 mM 2-mercapto-ethanol, 5 μg/mL eachof pepstatin, leupeptin, aprotinin, 20 μ/mL each of calpain inhibitors Iand II, and 2 mM benzamidine HCl). Cells were lysed in a French®pressure cell (SLM-Aminco®, Spectronic Instruments) at 10° C. Theextract was centrifuged in a Beckman JA-10 rotor at 9,000 rpm for 22minutes at 4° C. The supernatant was removed and centrifuged in aBeckman TI45 rotor at 36,000 rpm for 45 minutes at 40° C.

PDE4A was precipitated from the high-speed supernatant by the additionof solid ammonium sulfate (0.26 g/mL supernatant) while stirring in anice bath and maintaining the pH between 7.0 and 7.5. The precipitatedproteins containing PDE4A were collected via centrifugation in a BeckmanJA-10 rotor at 9,000 rpm for 22 minutes. The precipitate was resuspendedin 50 mL of Buffer G (50 mM MOPS pH 7.5, 10 μM ZnSO₄, 5 mM MgCl₂, 100 mMNaCl, 14.2 mM 2-mercaptoethanol, 2 mM benzamidine HCl, 5 μg/mL each ofleupeptin, pepstatin, and aprotinin, and 20 μg/mL each of calpaininhibitors I and II) and passed through a 0.45 μm filter.

The resuspended sample (50 to 100 mL) was loaded onto a 5×100 cm columnof Pharmacia SEPHACRYL® S-300 equilibrated in Buffer G. Enzyme activitywas eluted at a flow rate of 2 mL/min and pooled for laterfractionation.

The PDE4A isolated from gel filtration chromatography was applied to a1.6×20 cm column of Sigma Cibacron Blue Agarose-type 300 (10 mL)equilibrated in Buffer A (50 mM MOPS pH 7.5, 10 μM ZnSO₄, 5 mM MgCl₂,14.2 mM 2-mercaptoethanol, and 100 mM benzamidine HCl). The column waswashed in succession with 50 to 100 mL of Buffer A, 20 to 30 mL ofBuffer A containing 20 mM 5′-AMP, 50 to 100 mL of Buffer A containing1.5 M NaCl, and 10 to 20 mL of Buffer C (50 mM Tris HCl pH 8, 10 μMZnSO₄, 14.2 mM 2-mercaptoethanol, and 2 mM benzamidine HCl). The enzymewas eluted with 20 to 30 mL of Buffer C containing 20 mM cAMP.

The PDE activity peak was pooled, and precipitated with ammonium sulfate(0.33 g/mL enzyme pool) to remove excess cyclic nucleotide. Theprecipitated proteins were resuspended in Buffer X (25 mM MOPS pH 7.5, 5μM ZnSO₄, 50 mM NaCl, 1 mM DTT, and 1 mM benzamidine HCl), and desaltedvia gel filtration on a Pharmacia PD-10® column per manufacturer'sinstructions. The enzyme was quick-frozen in a dry ice/ethanol bath andstored at −70° C.

The resultant preparations were about >80% pure by SDS-PAGE. Thesepreparations had specific activities of about 10 to 40 pmol cAMPhydrolyzed per minute per milligram protein.

Preparation of PDE4B from S. cerevisiae

Yeast cells (150 g of yeast strain YI23 harboring HDUN2.32) were thawedby mixing with 100 mL glass beads (0.5 mM, acid washed) and 150 mL LysisBuffer (50 mM MOPS pH 7.2, 2 mM EDTA, 2 mM EGTA, 1 mM DTT, 2 mMbenzamidine HCl, 5 μg/mL each of pepstatin, leupeptin, aprotinin,calpain inhibitors I and II) at room temperature. The mixture was cooledto 4° C., transferred to a Bead-Beater®, and the cells lysed by rapidmixing for 6 cycles of 30 seconds each. The homogenate was centrifugedfor 22 minutes in a Beckman J2-21M centrifuge using a JA-10 rotor at9,000 rpm and 4° C. The supernatant was recovered and centrifuged in aBeckman XL-80 ultra-centrifuge using a TI45 rotor at 36,000 rpm for 45minutes at 4° C. The supernatant was recovered and PDE4B wasprecipitated by the addition of solid ammonium sulfate (0.26 g/mLsupernatant) while stirring in an ice bath and maintaining the pHbetween 7.0 and 7.5. This mixture was then centrifuged for 22 minutes ina Beckman J2 centrifuge using a JA-10 rotor at 9,000 rpm (12,000×g). Thesupernatant was discarded and the pellet was dissolved in 200 mL ofBuffer A (50 mM MOPS pH 7.5, 5 mM MgCl₂, 1 mM DTT, 1 mM benzamidine HCl,and 5 μg/mL each of leupeptin, pepstatin, and aprotinin). The pH andconductivity were corrected to 7.5 and 15-20 mS, respectively.

The resuspended sample was loaded onto a 1.6×200 cm column (25 mL) ofSigma Cibacron Blue Agarose-type 300 equilibrated in Buffer A. Thesample was cycled through the column 4 to 6 times over the course of 12hours. The column was washed in succession with 125 to 250 mL of BufferA, 125 to 250 mL of Buffer A containing 1.5 M NaCl, and 25 to 50 mL ofBuffer A. The enzyme was eluted with 50 to 75 mL of Buffer E (50 mM TrisHCl, pH 8, 2 mM EDTA, 2 mM EGTA, 1 mM DTT, 2 mM benzamidine HCl, and 20mM cAMP) and 50 to 75 mL of Buffer E containing 1 M NaCl. The PDEactivity peak was pooled, and precipitated with ammonium sulfate (0.4g/ML enzyme pool) to remove excess cyclic nucleotide. The precipitatedproteins were resuspended in Buffer X (25 mM MOPS pH 7.5, 5 μM ZnSO₄, 50mM NaCl, 1 mM DTT, and 1 mM benzamidine HCl) and desalted via gelfiltration on a Pharmacia PD-10® column per manufacturer's instructions.The enzyme pool was dialyzed overnight against Buffer X containing 50%glycerol. This enzyme was quick-frozen in a dry ice/ethanol bath andstored at −70° C.

The resultant preparations were about >90% pure by SDS-PAGE. Thesepreparations had specific activities of about 10 to 50 μmol cAMPhydrolyzed per minute per milligram protein.

Preparation of PDE4C from S. cerevisiae

Yeast cells (150 g of yeast strain YI30 harboring HDUN3.48) were thawedby mixing with 100 mL glass beads (0.5 mM, acid washed) and 150 mL LysisBuffer (50 mM MOPS pH 7.2, 2 mM EDTA, 2 mM EGTA, 1 mM DTT, 2 mMbenzamidine HCl, 5 μg/mL each of pepstatin, leupeptin, aprotinin,calpain inhibitors I and II) at room temperature. The mixture was cooledto 4° C., transferred to a BEAD-BEATER®, and the cells lysed by rapidmixing for 6 cycles of 30 sec each. The homogenate was centrifuged for22 minutes in a Beckman J2-21M centrifuge using a JA-10 rotor at 9,000rpm and 4° C. The supernatant was recovered and centrifuged in a BeckmanXL-80 ultra-centrifuge using a TI45 rotor at 36,000 rpm for 45 minutesat 4° C.

The supernatant was recovered and PDE4C was precipitated by the additionof solid ammonium sulfate (0.26 g/mL supernatant) while stirring in anice bath and maintaining the pH between 7.0 and 7.5. Thirty minuteslater, this mixture wag centrifuged for 22 minutes in a Beckman J2centrifuge using a JA-10 rotor at 9,000 rpm (12,000×g). The supernatantwas discarded and the pellet was dissolved in 200 mL of Buffer A (50 mMMOPS pH 7.5, 5 mM MgCl₂, 1 mM DTT, 2 mM benzamidine HCl, and 5 μg/mLeach of leupeptin, pepstatin, and aprotinin). The pH and conductivitywere corrected to 7.5 and 15-20 mS, respectively.

The resuspended sample was loaded onto a 1.6×20 cm column (25 mL) ofSigma Cibacron Blue Agarose-type 300 equilibrated in Buffer A. Thesample was cycled through the column 4 to 6 times over the course of 12hours. The column was washed in succession with 125 to 250 mL of BufferA, 125 to 250 mL of Buffer A containing 1.5 M NaCl, and then 25 to 50 mLof Buffer A. The enzyme was eluted with 50 to 75 mL of Buffer E (50 mMTris HCl pH 8, 2 mM EDTA, 2 mM EGTA, 1 mM DTT, 2 mM benzamidine HCl, and20 mM cAMP) and 50 to 75 mL of Buffer E containing 1 M NaCl. The PDE4Cactivity peak was pooled, and precipitated with ammonium sulfate (0.4g/mL enzyme pool) to remove excess cyclic nucleotide. The precipitatedproteins were resuspended in Buffer X (25 mM MOPS pH 7.2, 5 μM ZnSO, 50mM NaCl, 1 mM DTT, and 1 mM benzamidine HCl) and desalted via gelfiltration on a Pharmacia PD-10® column per manufacturer's instructions.The enzyme pool was dialyzed overnight against Buffer X containing 50%glycerol. This enzyme was quick-frozen in a dry ice/ethanol bath andstored at −70° C.

The resultant preparations were about >80% pure by SDS-PAGE. Thesepreparations had specific activities of about 10 to 20 4μmol cAMPhydrolyzed per minute per milligram protein.

Preparation of PDE4D from S. cerevisiae

Yeast cells (100 9 of yeast strain YI29 harboring HDUN4.11) were thawedby mixing with 150 mL glass beads (0.5 mM, acid washed) and 150 mL LysisBuffer (50 mM MOPS pH 7.2, 10 μM ZnSO₄, 2 mM MgCl₂, 14.2 mM2-mercaptoethanol, 2 mM benzamidine HCl, 5 gg/mL each of pepstatin,leupeptin, aprotinin, calpain inhibitors I and II) at room temperature.The mixture was cooled to 4° C., transferred to a Bead-Beater®, and thecells lysed by rapid mixing for 6 cycles of 30 sec each. The homogenatewas centrifuged for 22 minutes in a Beckman J2-21M centrifuge using aJA-10 rotor at 9,000 rpm and 4° C. The supernatant was recovered andcentrifuged in a Beckman XL-80 ultracentrifuge using a TI45 rotor at36,000 rpm for 45 minutes at 4° C. The supernatant was recovered andPDE4D was precipitated by the addition of solid ammonium sulfate (0.33g/mL supernatant) while stirring in an ice bath and maintaing the pHbetween 7.0 and 7.5. Thirty minutes later, this mixture was centrifugedfor 22 minutes in a Beckman J2 centrifuge using a JA-10 rotor at 9,000rpm (12,000×g). The supernatant was discarded and the pellet wasdissolved in 100 mL of Buffer A (50 mM MOPS pH 7.5, 10 μM ZnSO₄, 5 mMMgCl₂, 14.2 mM 2-mercaptoethanol, 100 mM benzamidine HCl, and 5 μg/mLeach of leupeptin, pepstatin, aprotinin, calpain inhibitor I and II).The pH and conductivity were corrected to 7.5 and 15-20 mS,respectively.

At a flow rate of 0.67 mL/min, the resuspended sample was loaded onto a1.6×20 cm column (10 mL) of Sigma Cibacron Blue Agarose-type 300equilibrated in Buffer A. The column was washed in succession with 50 to100 mL of Buffer A, 20 to 30 mL of Buffer A containing 20 mM 5′-AMP, 50to 100 mL of Buffer A containing 1.5 M NaCl, and then 10 to 20 mL ofBuffer C (50 mM Tris HCl, pH 8, 10 lM ZnSO₄, 14.2 mM 2-mercaptoethanol,2 mM benzamidine HCl). The enzyme was eluted with 20 to 30 mL of BufferC containing 20 mM cAMP.

The PDE4D activity peak was pooled and precipitated with ammoniumsulfate (0.4 g/mL enzyme pool) to remove excess cyclic nucleotide. Theprecipitated proteins were resuspended in Buffer X (25 mM MOPS pH 7.2, 5μM ZnSO₄, 50 mM NaCl, 1 mM DTT, and 1 mM benzamidine HCl) and desaltedvia gel filtration on a Pharmacia PD-10® column per manufacturer'sinstructions. The enzyme pool was dialyzed overnight against Buffer Xcontaining 50% glycerol. This enzyme preparation was quick-frozen in adry ice/ethanol bath and stored at −70° C.

The resultant preparations were about >80% pure by SDS-PAGE. Thesepreparations had soecific activities of about 20 to 50 zmol cAMPhydrolyzed per minute per milligram protein.

Purification of PDE5 from S. cerevisiae

Cell pellets (29 g) were thawed on ice with an equal volume of LysisBuffer (25 mM Tris HCl, pH 8, 5 mM MgCl₂, 0.25 mM DTT, 1 mM benzamidine,and 10 μM ZnSO₄). Cells were lysed in a Micro-fluidizer® (MicrofluidicsCorp.) using nitrogen at 20,000 psi. The lysate was centrifuged andfiltered through 0.45 gm disposable filters. The filtrate was applied toa 150 mL column of Q SEPHAROSE® Fast-Flow (Pharmacia). The column waswashed with 1.5 volumes of Buffer A (20 mM Bis-Tris Propane, pH 6.8, 1mM MgCl₂, 0.25 mM DTT, 10 μM ZnSO₄) and eluted with a step gradient of125 mM NaCl in Buffer A followed by a linear gradient of 125-1000 mMNaCl in Buffer A. Active fractions from the linear gradient were appliedto a 180 mL hydroxyapatite column in Buffer B (20 mM Bis-Tris Propane(pH 6.8), 1 mM MgCl₂, 0.25 mM DTT, 10 μM ZnSO₄, and 250 mM KCl ). Afterloading, the column was washed with 2 volumes of Buffer B and elutedwith a linear gradient of 0-125 mM potassium phosphate in Buffer B.Active fractions were pooled, precipitated with 60% ammonium sulfate,and resuspended in Buffer C (20 mM Bis-Tris Propane, pH 6.8, 125 mMNaCl, 0.5 mM DTT, and 10 μM ZnSO₄). The pool was applied to a 140 mLcolumn of SEPHACRYL® S-300 HR and eluted with Buffer C. Active fractionswere diluted to 50% glycerol and stored at−20° C.

The resultant preparations were about 85% pure by SDS-PAGE. Thesepreparations had specific activities of about 3 Wmol cGMP hydrolyzed perminute per milligram protein.

Preparation of PDE7 from S. cerevisiae

Cell pellets (126 g) were thawed and resuspended at room temperature forabout 30 minutes with an equal volume of Lysis Buffer (50 mM Tris HCl,pH 8, 1 mM EDTA, 1 mM DTT, 50 mM NaCl, 2 mM benzamidine HCl, and 5 μg/mLeach of pepstatin, leupeptin, and aprotinin). The cells were lysed at0-4° C. with the aid of glass beads (125 mL) in a Bead-Beater® for 6×30second cycles. The lysate was centrifuged and filtered through 0.45 μmdisposable filters. The filtered extract (178 mL) was distributed into 4mL aliquots, quick-frozen with dry ice, and stored in a freezer at −70°C. These preparations were stable to several cycles of freezing andthawing and had specific activities of about 50 to 100 pmol cAMPhydrolyzed per minute per milligram protein.

Lipopolysaccharide-Stimulated TNFα Release from Human Peripheral BloodLymPhocytes

To assess the ability of a compound to reduce TNFα secretion in humanperipheral blood lymphocytes (PBL), the following tests were performed.Previous studies have demonstrated that incubation of human DLBL withcAMP-elevating agents, such as prostaglandin E21, forskolin,8-bromo-cAMP, or dibutryl-cAMP, inhibits the secretion of TNFα by thecells when stimulated by lipopolysaccharide (LPS; endotoxin)Accordingly, preliminary experiments have been performed to demonstratethat selective PDE4 inhibitors, such as rolipram, inhibit LPS-inducedTNFα secretion from human lymphocytes in a dose-dependent fashion.Hence, TNFα secretion from human PBL was used as a standard for theability of a compound to elevate intracellular CAMP concentrationsand/or to inhibit PDE4 activity within the cell.

Heparinized blood (approximately 30 mL) drawn from human volunteers wasmixed 1:1 with Dulbecco's modified phosphate-buffered saline. Thismixture was mixed 1:1 with HISTOPAQUE® and centrifuged at 1,500 rpm atroom temperature without braking in the swinging bucket of a Beckmanmodel TJ6 centrifuge. Erythrocytes were centrifuged to the bottom of thetubes, and serum remained at the surface of the tubes. A layercontaining lymphocytes sedimented between the serum and HISTOPAQUE®layers, and was removed by aspiration to a fresh tube. The cells werequantified and adjusted to 3×10⁶ cells/mL and a 100 μL aliquot is placedinto the wells of a 96 well plate. Test compounds and RPMI media(Gibco/BRL Life Sciences) are added to each of the wells 15 minutesprior to addition of bacterial LPS (25 mg/mL). The mixture was allowedto incubate for 20 hours at 37° C. in a humidified chamber. The cellsthen were separated by centrifuging at 800 rpm for 5 minutes at roomtemperature. An aliquot of 180 μL of supernatant was-transferred to anew plate for determination of TNFα concentration. TNFα protein in thecell supernatant fluids was measured using a commercially availableenzyme-linked immunosorbent assay (ELISA) (CYTOSCREEN® Immunoassay Kitfrom Biosource International).

The cell-based assay provided the following results for variouspyrrolidine compounds of the present invention. The EC₅₀ values (i.e.,effective concentration of the compound capable of inhibiting 50% of thetotal TNFα) illustrate the ability of the present compounds to inhibitLPS-stimulated TNFα release from human PBL.

The table below illustrates the ability of compounds of formula (II) toinhibit PDE4 activity and TNFα release in vitro. In the following table,the IC₅₀ values were determined against human recombinant PDE4.

Sample PDE4 IC₅₀ PBL/TNFα EC₅₀ Number¹⁾ Stereochemistry (M × 10⁻⁹) (M ×10⁻⁹) 1 Absolute, as drawn 87.0 1,205.8 2 Absolute, as drawn 260.01,900.0 3 Relative stereochem- 180.0 3,261.7 istry as drawn; racemic 4Relative, stereochem- 190.0 3,611.5 istry as drawn; racemic 5 Relative,stereochem- 75.0 1,551.3 istry as drawn; racemic 6 Relative, stereochem-75.0 3,657.5 istry as drawn; racemic 7 Absolute, as drawn 5,800.0 8Absolute, as drawn 784.0 909.6 9 Absolute, as drawn 13,000.0 10Absolute, as drawn 7,900.0 11 Absolute, as drawn 3,700.0 12 Absolute, asdrawn 2,600.0 13 Absolute, as drawn 1,000.0 2,339.5 14 Absolute, asdrawn 900.0 2,981.5 15 Relative stereochem- 4.3 108.8 istry as drawn;race- mic, mixture of ether isomers 16 Relative stereochem- 7.3 46.4istry as drawn; racemic, mixture of ether isomers 17 Absolute, as drawn2,211.6 3,447.3 18 Absolute, as drawn 1,027.3 5,101.6 19 Absolute, asdrawn 1,974.0 1,951.1 20 Absolute, as drawn 536.0 170.0 21 Absolute, asdrawn 16.2 278.0 22 Absolute, as drawn 520.4 164.0 23 Absolute, as drawn1,592.2 24 Absolute, as drawn; 1.6 40.0 mixture of ether iso- mers 25Absolute, as drawn; 2.8 12.2 mixture of ether iso- mers 26 Absolute, asdrawn; 35.0 106.0 mixture of ether iso- mers 27 Absolute, as drawn; 1.836.0 mixture of ether iso- mers 28 Absolute, as drawn 23.0 241.0 29Absolute, as drawn 4.9 78.0 30 Absolute, as drawn 100.0 440.0 31Absolute, as drawn 3.6 35.0 32 Absolute, as drawn 1,000.0 801.0 33Absolute, as drawn 2,100.0 34 Absolute, as drawn 402.6 250.0 35Absolute, as drawn 35.6 20.3 36 Absolute, as drawn 187.2 1,600.0 37Absolute, as drawn .768 72.0 38 Absolute, as drawn 5.9 36.0 39 Absolute,as drawn 2.7 48.1 40 Absolute, as drawn 98.4 139.1 41 Absolute, as drawn27.0 266.9 42 Absolute, as drawn 7.5 171.7 43 Absolute, as drawn 12.5145.8 44 Absolute, as drawn 41.2 238.0 45 Absolute, as drawn 247.6 694.046 Absolute, as drawn 1,805.9 13,317.0 47 Absolute, as drawn 2,727.420,000.0 48 Absolute, as drawn 89.7 446.0 49 Absolute, as drawn 14.326.2 50 Absolute, as drawn 44.8 151.2 51 Absolute, as drawn 44.7 72.6 52Absolute, as drawn 26.7 53 Absolute, as drawn; 116.3 112.6 mixture oftetrahydro- furyl isomers 54 Absolute, as drawn; 464.7 mixture of 2,2-dimethyl-4-oxo-4- pyrrolidin-1-yl- butyric acid and 3,3-dimethyl-4-oxo-4- pyrrolidin-1-yl- butyric acid amides 55 Absolute, asdrawn 1,842.1 56 Absolute, as drawn 4.0 57 Absolute, as drawn 95.6 58Absolute, as drawn 59 Racemic; relative 58.0 170.0 stereochemistry asshown 60 Racemic; relative 74.0 44.0 stereochemistry as shown 61Racemic; relative 18.3 57.8 stereochemistry as shown 62 Racemic,relative 6.8 10.2 stereochemistry as shown 63 Racemic, relative 51.4267.4 stereochemistry as shown, nonbornyl resi- due racemic 64 Racemic,relative 8.5 36.2 stereochemistry as shown, nonbornyl resi- due racemic65 Racemic, relative 220.0 181.0 stereochemistry as shown 66 Absolute14.0 71.6 stereochemistry as shown 67 Absolute stereochem- 514.7 603.3istry as shown 68 Absolute stereochem- 61.1 169.9 istry as shown 69Absolute stereochem- 13.3 57.0 istry as shown 70 Absolute stereochem-498.5 547.2 istry as shown; single undefined alcohol isomer 1 71Absolute stereochem- 1,707.2 istry as shown; single undefined alcoholisomer 2 72 Absolute, as drawn 2,452.6 73 Absolute, as drawn 9,131.0 74Absolute, as drawn 352.3 557.3 75 Absolute, as drawn 45.1 121.0 76Absolute, as drawn 36.6 173.0 77 Absolute, as drawn 188.7 580.0 78Absolute, as drawn 760.1 1,288.6 79 Absolute, as drawn 1,639.0 2,366.680 Absolute, as drawn 300.0 272.4 81 Absolute, as drawn 700.0 624.8 82Absolute, as drawn 389.8 490.0 83 Absolute, as drawn 172.0 51.0 84Absolute, as drawn 21.7 40.0 85 Absolute, as drawn 3,576.8 86 Absolute,as drawn 6,077.6 87 Absolute, as drawn 896.6 934.4 88 Absolute, as drawn953.4 629.5 89 Absolute, as drawn 699.0 860.0 90 Absolute, as drawn 69.461.0 91 Absolute, as drawn 150.0 44.0 92 Absolute, as drawn 439.4 93Absolute, as drawn 33.1 7.8 94 Absolute 238.2 1,800.0 stereochemistry asshown ¹⁾See Appendix A for structure of each sample

The data presented above shows that the present compounds are potentinhibitors of PDE4, e.g., the compounds have an IC₅₀ vs. humanrecombinant PDE4 of about 700 pM to about 15 μM. Preferred compoundshave an IC₅₀ of about 100 nM or less, and especially preferred compoundshave an IC₅₀ of about 50 nM or less.

Similarly, preferred compounds have a PBL/TNFα EC₅₀ about 500 nM orless, and preferably about 200 nM or less. More preferred compounds havea PBL/TNFα EC₅₅ of about 100 nM or less.

To achieve the full advantages of the present invention, the compoundshave an IC₅₀ vs. human recombinant PDE4 of about 100 nM or less and aPBL/TNFα EC₅₀ of about 500 nM or less. More preferably, the compoundshave an IC₅₀ of about 50 nM or less and a PBL/TNFα EC₅₀ of about 100 nMor less.

ANIMAL MODELS Assay for Inhibition of Serum TNFα Levels in Manunals(Mouse/TNFα ED₅₀ (mg/kg )

In order to assess the ability of a compound to reduce serum TNFα levelsin mammals, the following protocol was employed. Those skilled in theart appreciate that previous studies have demonstrated that incubationof LPS-activated human monocytes with agents that can elevate cAMP, likePGE2, forskolin, and the dbcAMP, inhibited secretion of TNFα. PDE4inhibitors like rolipram, which also elevate cAMP, have been found toinhibit serum TNFα as well. Rolipram has also been found to inhibitsecretion of TNFα from LPS-activated mouse macrophages. Accordingly, invivo efficacy of a PDE4 reducing compound was shown by dosing withcompound and measuring reduction of serum TNFα levels in LPS-injectedmice. Female C3H mice, 20-25 gm body weight, were fasted overnight anddosed intraperitoneally with test compound in appropriate vehicle 60minutes before LPS injection. Five μg of LPS was then injectedintraperitoneally into the mice. Ninety minutes after LPS injection,mice were bled from the heart. Blood was allowed to clot overnight at40C. Samples were centrifuged for 10 minutes in a microcentrifuge andthe serum removed and stored at−20° C. until analysis. Serum levels ofTNFα were subsequently measured using a commercially available ELISA kit(Genzyme) following the protocol enclosed in the kit. The percent ofinhibition of serum TNFα levels caused by the compound was determinedrelative to serum TNFα levels in control mice receiving vehicle alone.

Combined Mouse Endotoxin-stimulated TNFα Release and Locomotor ActivityAssay (ED₅₀ (mg/kg))

The purpose of this study was to determine the efficacy of PDE4inhibitors in vivo in an LPS mouse model together with a determinationwith respect to central nervous system (CNS) side-effects manifested bya decrease in spontaneous mobility.

The test animals were female Balb/c mice, having an average weight ofabout 20 g. The PDE4 inhibitors, formulated in 30% Cremophor® EL, wereadministered via intraperitoneal (i.p.) injections at doses of 0.1, 1.0,10.0, and 100 mg/kg. Individual dose volumes (about 150 μL) wereadjusted based on the body weights measured. One hour later, 5 mg/kg LPSin a final volume of 200 μL was injected via the tail vein to eachanimal. Ninety minutes following the LPS treatment, the animals werebled and serum samples were collected before being stored at−70° C.until assayed.

For efficacy determination, the serum samples were diluted two-fold andTNFα levels were determined using the CYTOSCREEN® Immunoassay Kit(Biosource International). The data were averaged between triplicatesample subjects for each of the tested compounds.

Movement of the X-Y plane, or rearing up on the hind legs, wasquantified by counting the number of “light-beam” crosses per unit oftime. A decrease in the number of activity events is directlyproportional to the mobility or immobilization of the animal. Thequantitative scoring correlated well with the subjective measurementsdescribed above.

The following table summarizes the Mouse/TNFα ED₅₀ (mg/kg) resultsobtained by the above-described:

Mouse/TNFα Sample Number¹⁾ ED₅₀ (mg/kg) ED₅₀ (mg/kg)³⁾ 29 — 9.8 31 3 8361 0.2 >50 62 0.08 >50 66 5 >50 67 — >50 68 12 20 69 7 <0.5 ³⁾effectivedose, in mg/kg, that decreases spontaneous mobility 50% of control.

It also was determined that compounds of formula (II) have fewer centralnervous system side effects compared to rolipram and to compoundsdisclosed in Feldman et al. U.S. Pat. No. 5,665,754. It also was foundthat central nervous system activity is related to the absolutestereochemistry of compounds.

It is known that stereoisomers of drugs can have substantially differentbiological activities e.g., potency, selectivity, absorption,distribution, metabolism, execution, and side effect profiles. In thepresent invention, the enantiomers and diastereomers represented bycompounds (A)-(D) in the following table were tested for effects on invitro PDE activity, cell-based LPS/TNFα release from human peripheralblood lymphocytes (PBLs), mouse mobility, and ferret emesis.

As shown in the following table, compounds (C) and (A) (i.e., Samples 66and 69, respectively) show similar inhibition of PDE4 and LPS-stimulatedTNFα release, but substantially different behavioral profiles. Compounds(C) and (A), which exhibit less CNS activity, are derived from thepredominant product of the [3+2] azomethine ylide cyclization to thechiral α, β-unsaturated amide. Thus, the absolute stereochemistry of aPDE4 inhibitor of the present invention contributes significantly to thebehavioral profile of the compound.

PDE4 Mouse/TNFα CNS Side Examples Compound IC₅₀ (nM) ED₅₀ (mg/kg)Effects¹⁾ (A)

13.3 7 Severe (C)

14.0 5 No effect (B)

61.1 12 No effect (D)

514.7 — No effect Sample No. 62

6.8 0.08 Little to no effect (at 50 mg/kg) Sample No. 61

18.3 0.2 Little to no effect (at 50 mg/kg) ¹⁾CNS side effects weredetermined by a subjective assessment of mouse immobility followinginjection of compounds i.p. at 1, 10, and 100 mg/kg doses. Mobility (orlack thereof) assessment was scored by observing the following: reducedexploratory behavior, fattened posture, prone positioning, ruffled fur,etc. No apparent effects were noted over the 60 minutes time frame ofassessment with Examples 8(C), 8(D), and 8(B). However, mice wereeffected at all doses when given Example 8(A). Furthermore, at thehighest dose of Example 8(A), mice became moribund and died within 10minutes of treatment.

The data presented above show that compounds of formula (II) are potentand selective inhibitors of PDE4. As an important added advantage, thecompounds of formula (II) also reduced or eliminated the adverse CNSside effects associated with prior PDE4 inhibitors. Compounds of formula(II) were further tested for emetogenic properties in animal models tofurther illustrate the efficacy of the compounds. The method and resultsof the emetogenic test are set forth below.

Emetic Modeling in the Ferret Following Oral and Intravenous Dosing WithPDE4-Selective Inhibitors

This study was conducted to investigate the emetogenic properties ofPDE4 inhibitors in vivo. The ferret previously has been established as avaluable tool for assessing emesis following exposure to test compounds.Previous studies indicated that the emetic response of a ferret to manyPDE4 inhibitors is predictive of the disposition of humans toward thesame test compounds. Therefore, lack of and/or decrease in emeticpotential of test compounds in ferrets predicts a favorable nonemeticeffect in humans. Emesis is a complex physiological response to noxiousagents that can be intiated peripherally or centrally. Hence,PDE4-selective agents were tested when administered both intravenouslyor orally.

The test animals were adult, castrated, and descented male ferrets(species=Mustela putorius furo, Strain=Sable) ranging in weight fromabout 1 to 1.5 kg. The tests were performed in quadruplicate on animalsthat were naive to PDE4 inhibitors. The PDE4 inhibitors were formulatedin 10% Polyoxyl-35 castor oil (CREMOPHOR® EL, available from BASFCorporation, Parsippany, N.J.) in phosphate buffered saline (PBS), andwere administered via i.v. injections into an indwelling cathetersurgically positioned in the right external jugular vein at a rate of0.66 mL per kg body weight. PDE4 inhibitors for oral consumption wereformulated in 30% CREMOPHOR® EL in PBS, and administered by intubatinganimals with a 16-gauge feeding needle into the stomach. The animalsreceived the PDE4 inhibitors in a volume of 1.33 mL per kg body weight.

All animals were fasted for 8 to 12 hours prior to administration ofPDE4 inhibitors. Following administration of a PDE4 inhibitor, emeticand behavioral responses were quantified for three hours post dosing.The total number of emetic responses and vomiting episodes werequantified during the observation interval. In addition, latency time tofirst emetic episode, duration of emesis episodes, and gross behavioralchanges including ataxia, profuse and viscous salivation, mouth clawing,hyperventilation, backward walking, flattened body posture,hyperactivity, lip licking, and general appearance were recorded.

For comparative purposes, the emetogenic effect of Samples 66 and 69were tested intravenously at 1.0, 2.5, 5.0, and 10 mg/kg and orally at2.5, 10, 17, and 25 mg/kg. The results are summarized in the followingtable:

COMPARATIVE RESULTS Number of Emetic Events Vomits Retches TotalResponders Compound (A) (Sample 69) Oral (mg/kg) 2.5 0 0 0 0/4 10.0 5 2732 3/4 17.0 7 51 58 3/4 25.0 26 88 114 4/4 Intravenous (mg/kg) 1.0 0 0 00/4 2.5 0 3 3 1/4 5.0¹⁾ 0 300 300 2/2 10.0 — — — — Compound (C) (Sample66) Oral (mg/kg) 2.5 0 0 0 0/4 10.0 8 14 22 2/4 17.0 1 17 18 2/3 25.0 1261 73 4/4 Intravenous (mg/kg) 1.0 0 0 0 0/4 2.5 0 0 0 0/4 5.0¹⁾ 0 10 102/4 10.0 4 27 31 4/4 ¹⁾Only two ferrets were dosed intravenously with 5mg/kg compound (A) because of the severity of the responses. Therefore,10 mg/kg Example 8 (A) was not administered intravenously.

In general, both compounds (C) and (A), delivered either orally or viaintravenous injection, produced a clear dose response in terms of emeticbehavior. Compound (A) produced a much stronger emetic response thancompound (C). This was readily apparent when the responses to oraldosing was compared. For example, at a dose of 25 mg/kg body weight,compound (A) produced more retching and vomiting episodes than the sameoral dose of compound (C). In addition, the number of retches andvomiting events per episode was much greater for compound (A) thancompound (C) in this dose group. A similar trend was apparent at oraldosages of 17 and 11 mg/kg body weight, with compound (A) exhibiting astronger response than compound (C). There were no apparent differencesobserved between the lowest dosed groups for both molecules. In thesecases, some minor lip licking/mouth pawing was evident with bothcompounds, but no emetic responses were observed.

The results of oral dosing contrast markedly with that of intravenousdosing. At an intravenous dose of 5 mg/kg body weight of compound (A),one of the tested animals died almost immediately after dosing (within 5minutes), whereas the second animal was clearly distressed, butrecovered after 3 hours. The distress can be attributed either to anacute toxicity event or to an exaggerated pharmacological response tocentrally mediated emesis. It also was noted that the distressed andlabored breathing in these dosed animals was difficult to distinguishfrom extreme retching behavior. The effects were not nearly as severewith intravenous administration of compound (C) as shown in the abovetable. Although all animals exhibited emetic behavior at the 10 mg/kgbody weight dose with compound (C), none displayed the distressassociated with the 5 mg/kg dose of compound (A). With the exception ofthe 5 mg/kg body weight dose of compound (A), all of the animalsrecovered from their treatment and appeared normal.

Example 101 Example 264 Example 109 Example 268 Example 195 Assay PDE4BIC₅₀ (μM) 0.011 0.003 0.02 0.015 0.007 Cell based EC₅₀ 0.03 0.010 0.030.006 0.03 (μM) Mouse LPS 3 1 5 5 9 Challenge ED₅₀ (mg/kg) Mouse 100<100 100 100 100 Inhibition of Spontaneous Mobility ED₅₀ (mg/kg)

The results summarized in the above tables show that the compounds ofthe present invention are useful for selectively inhibiting PDE4activity in a mammal, without exhibiting the adverse CNS and emeticeffects associated with prior PDE4 inhibitors.

Obviously, many modifications and variations of the invention ashereinbefore set forth can be made without departing from the spirit andscope thereof and, therefore, only such limitations should be imposed asare indicated by the appended claims.

What is claimed is:
 1. A compound having a formula:

wherein R₁ is selected from the group consisting of hydrogen, loweralkyl, bridged alkyl, aryl, cycloalkyl, a 4-, 5-, or 6-memberedsaturated heterocycle, heteroaryl, C₁₋₄alkylenearyl, C₁₋₄alkyleneOaryl,C₁₋₄alkyleneheteroaryl, C₁₋₄alkyleneHet, C₂₋₄alkylenearylOaryl,C₁₋₄alkylene bridged alkyl, C₁₋₄alkylenecycloalkyl, substituted orunsubstituted propargyl, substituted or unsubstituted allyl, andhalocycloalkyl; R² is selected from the group consisting of hydrogen,methyl, and halo-substituted methyl, CHF₂; R₃ is selected from the groupconsisting of C(═O)OR⁷, C(═O)R⁷, NHC(═O)OR⁷, C₁₋₃alkyleneC(═O)OR⁸,C₁₋₃alkyleneC(═O)R⁸, C(═NH)NR⁸R⁹, C(═O)NR⁸R⁹, C(═O)—C(═O)NR⁸R⁹,C(═O)C(═O)OR⁸, C₁₋₄alkyleneOR⁸, aryl, C₁₋₃alkylenearyl,C₁₋₃alkyleneheteroaryl, SO₂heteroaryl, Het, and heteroaryl; R⁴ isselected from the group consisting of hydrogen, lower alkyl, haloalkyl,cycloalkyl, and aryl; R⁵ is selected from the group consisting ofhydrogen, lower alkyl, alkynyl, haloalkyl, hydroxyalkyl, cycioalkyl, andaryl; R⁶ is selected from the group consisting of hydrogen, lower alkyl,and C(═O)R⁷; R⁷ is selected from the group consisting of lower alkyl,branched or unbranched, C₁₋₄alkylenearyl, cycloalkyl, Het,C₁₋₄alkylenecycloalkyl, heteroaryl, and aryl, each optionallysubstituted with one or more of OC(═O)R⁸, C(═O)OR⁸, OR⁸, NR⁸R⁹, or SR⁸;R⁸ and R⁹, same or different, are selected from the group consisting ofhydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, C(═O)Oalkyl,C(═O)—Oaryl, C(═O)alkyl, alkylSO₂, haloalkylSO₂, C(═O)—C₁₋₃alkylenearyl,C(═O)OC₁₋₄alkylenearyl, C₁₋₄alkylenearyl, and Het, or R⁸ and R⁹ togetherform a 4-membered to 7-membered ring; R¹⁰ is selected from the groupconsisting of hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, C(═O)alkyl,C(═O)cycloalkyl, C(═O)aryl, C(═O)Oalkyl, C(═O)Ocycloalkyl, C(═O)aryl,CH₂OH, CH₂Oalkyl, CHO, CN, NO₂, and SO₂R¹¹; R¹¹ is selected from thegroup consisting of alkyl, cycloalkyl, trifluoromethyl, aryl, aralkyl,and NR⁸R⁹; and salts and solvates thereof.
 2. The compound of claim 1having the structure:


3. The compound of claim 1 wherein R¹ is selected from the groupconsisting of:


4. The composition of claim 1 wherein R³ is selected from the groupconsisting of:


5. The compound of claim 1 wherein R⁴ is selected from the groupconsisting of hydrogen, methyl, trifluoromethyl, cyclopropyl, benzyl,and phenyl.
 6. The compound of claim 1 wherein R⁵ is lower alkyl.
 7. Thecompound of claim 1 wherein R⁶ is selected from the group consisting ofhydrogen, acetyl, and benzoyl.
 8. The compound of claim 1 wherein R⁷ islower alkyl.
 9. The compound of claim 1 wherein R⁸ and R⁹,independently, are hydrogen, lower alkyl, C(═O)C₁₋₃alkylenearyl,C(═O)Oaryl, aryl, heteroaryl, Het, or cycloalkyl, or together form a5-membered or 6-membered ring.
 10. The compound of claim 1 wherein R¹ isselected from the group consisting of cyclopentyl, tetrahydrofuryl,indanyl, norbornyl, phenethyl, phenylbutyl, methylenecyclopropyl,methylenetetrahydrofuryl, ethylenethienyl, C₁₋₄alkylenecyclopentyl,methyleneindanyl, C₁₋₄alkylenephenyl, phenylpropargyl, phenylallyl,3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)methyl, C₁₋₄alkylenephenoxy,C₁₋₄alkylenebiphenyl, C₁₋₄alkylenecyclohexyl, pyranyl, methylene bridgedalkyl, tetrahydronaphtyl, decahydronaphthyl, and C₁₋₆alkyl, optionallysubstituted with one or more phenyl, hydroxy, methoxy, methyl, ethyl,trifluoromethyl, fluoro, phenoxy, t-butyl, methoxy, cyclopropyl, andhalophenyl; R² is selected from the group consisting of methyl anddifluoromethyl; R³ is selected from the group consisting of CO₂CH₃,C(═O)CH₂OH, C(═O)CH(CH₃)OH, C(═O)C(CH₃)₂OH, C(═O)C(═O)NH₂, C(═O)C(═O)OH,C(═O)CH₂NH₂, C(═O)CH—(OH)CH₂OH, C(═O) CH(OH)CH₂CH₂CH₃,

R⁴ is hydrogen; R⁵ is methyl; R⁶ is hydrogen; R⁷ is methyl; R⁸ and R⁹,independently, are selected from the group consisting of hydrogen andlower alkyl, or form a 5-membered or 6-membered ring, and R¹⁰ ishydrogen.
 11. The compound of claim 1 selected from the group consistingof:1-[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(1-hydroxy-1-methylethyl)-3-(S)-methylpyrrolidin-1-yl]-2-hydroxyethanoneMethyl2-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoacetateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylate2-[(3R)-3-((1R)-1-Hydroxyethyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-1-phenylethylacetate1-[(3R)-3-((1R)-1-Hydroxyethyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxy-2-phenyl-ethan-1-one1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyethan-1-one2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-methyl-2-oxo-ethylacetate1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-hydroxypropan-1-one{[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]carbonyl}cyclopropylacetate3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinylhydroxycyclopropyl ketone2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1,1-dimethyl-2-oxo-ethylacetate1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxy-2-methylpropan-1-oneMethyl2-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-acetate2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoaceticacid2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoacetamide2-{(3S,4S)-3-((R)-1-Hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)-phenyl]-3-methylpyrrolidin-1-yl}-2-oxo-acetamide2-((3S,4S)-3-((R)-1-Hydroxyethyl)-4-{4-methoxy-3-[3-(4-trifluoromethyl-phenyl)prop-2-ynyloxy]-phenyl}-3-methylpyrrolidin-1-yl)-2-oxo-acetamide2-[(3S,4S)-4-{3-[3-(4-Fluorophenoxy)propoxy]-4-methoxyphenyl}-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-oxo-acetamide2-[(3S,4S)-4-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-oxo-acetamide2-{(3S,4S)-3-((R)-1-Hydroxyethyl)-4-[3-(indan-2-yloxy)-4-methoxyphenyl]-3-methylpyrrolidin-1-yl}-2-oxo-acetamide2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-N-methyl-2-oxoacetamide1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-piperidylethane-1,2-dione2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-N-cyclopentyl-2-oxoacetamide2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-N-benzylacetamideN-{(1R)-2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-butyl-2-oxoethyl}(phenylmethoxy)carboxamide(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-aminohexan-1-oneN-{(1R)-2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-(methylethyl)-2-oxoethyl}(phenylmethoxy)carboxamide(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-amino-3-methylbutan-1-one2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-1-cyclohexyl-2-oxoethylacetate1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-cyclohexyl-2-hydroxyethan-1-one1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2R)-2-cyclohexyl-2-acetoxyethan-1-one(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-cyclohexyl-2-hydroxyethan-1-oneN-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-1-butyl-2-oxoethyl}(phenylmethoxy)carboxamide1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-aminohexan-1-one(1R)-2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-butyl-2-oxoethylacetate(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyhexan-1-oneN-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-2-oxo-1-benzylethyl}(phenylmethoxy)carboxamide1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-amino-3-phenylpropan-1-oneN-{(1R)-2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-1-benzylethyl}(phenylmethoxy)carboxamide(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-amino-3-phenylpropan-1-one2-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxo-1-propylethylacetate1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxypentan-1-one1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-(phenylmethoxy)propan-1-one1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-(hydroxy)propan-1-oneN-((1R)-2-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-(tert-butyl)-2-oxoethyl)(tert-butoxy)carboxamide(2R)-1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-amino-3,3-dimethylbutan-1-oneN-{2-[(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1R)-2-oxo-1-[(phenylmethoxy)methyl]ethyl}(tert-butoxy)carboxamideN-(2-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-2-oxo-1-[(phenylmethoxy)methyl]ethyl)(tert-butoxy)carboxamideN-(2-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1R)-1-(hydroxymethyl)-2-oxoethyl)(tert-butoxy)carboxamide1{(3S,4S)-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2R)-2-amino-3-hydroxypropan-1-onehydrochloride2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-cyclohexyl-2-oxoethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-cyclohexyl-2-hydroxyethan-1-one(1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-cyclohexyl-2-oxoethylacetate(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-cyclohexyl-2-hydroxyethan-1-oneN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-butyl-2-oxoethyl)(phenylmethoxy)carboxamide(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]3-methylpyrrolidinyl}-2-amino-hexan-1-oneN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-(methylethyl)-2-oxoethyl)(phenylmethoxy)carboxamide(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-amino-3-methylbutan-1-one1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-acetylthioethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-acetylthioethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-sulfanylethan-1-oneN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxo-ethyl)(phenylmethoxy)carboxamide1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl)-2-aminoethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-[(methylsulfonyl)amino]ethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-{[(trifluoromethyl)sulfonyl]amino}ethan-1-one1-{3-(1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(dimethylamino)ethan-1-oneN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-methyl-2-oxoethyl)(phenylmethoxy)carboxamide1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-aminopropan-1-oneN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl})-1-methyl-2-oxoethyl)(phenylmethoxy)carboxamide(2R)-1-{3-((1R)-1Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-aminopropan-1-oneN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-(methylethyl)-2-oxoethyl)(phenylmethoxy)carboxamide1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-amino-3-methylbutan-1-oneN-(-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-(2-methylpropyl)-2-oxoethyl)(phenylmethoxy)carboxamide1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-amino-4-methylpentan-1-oneN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl} -1-(2-methypropyl)-2-oxoethyl)(phenylmethoxy)carboxamide(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-amino-4-methylpentan-1-oneN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-butyl-2-oxoethyl)(phenylmethoxy)carboxamide1-{3-((1R)-1-Hydroxyethyl)(3S4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-aminohexan-1-oneN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-(1R)-cyclohexyl-2-oxoethyl)(phenylmethoxy)carboxamide(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-amino-2-cyclohexylethan-1-oneN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-(1S)-cyclohexyl-2-oxoethyl)(phenylmethoxy)carboxamide1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-amino-3,3-dimethylbutan-1-one1-{(3R)-3-((1R)-1-Hydroxyethyl)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(phenylmethoxy)ethan-1-one1-[(3R)-3-((1R)-1-Hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(phenylmethoxy)ethan-1-one2-Benzyloxy-1-(3-((1R)-1-hydroxyethyl)-(3S,4S)-4-[4-methoxy-3-(1-methylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl)ethanone1-((3R)-3-((1R)-1-Hydroxyethyl)-4-{4-methoxy-3-[(methylcyclopropyl)methoxy]phenyl}-3-methylpyrrolidinyl)-2-hydroxyethan-1-one2-Benzyloxy-1-[(3S,4S)-4-[3-(2-cyclopropylethoxy)-4-methoxyphenyl]-3-((1R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone1-{(3R)-3-((1R)-1-Hydroxyethyl)-4-[3-(2-cyclopropylethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one1-{(3R)-3-((1R)-1-Hydroxyethyl)-4-[3-(2-cyclopentylethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one1-[(3S,4S)-4-[3-(2-cyclopentylethoxy)-4-methoxyphenyl]-3-((1R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone2-Benzyloxy-1-[4-(S)-[3-(bicyclo[4.1.0]hept-7-ylmethoxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone1-[4-(S)-[3-(Bicyclo[4.1.0]hept-7-ylmethoxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone2-Benzyloxy-1-[4-(S)-[3-(bicyclo[3.1.0]hex-6-ylmethoxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone1-[4-(S)-[3-(Bicyclo[3.1.0]hex-6-ylmethoxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone2-Benzyloxy-1-[4-(S)-[3-(4-tert-butylcyclohexyloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone1-[4-(S)-[3-(4-tert-Butylcyclohexyloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-2-methylpyrrolidin-1-yl]-2-hydroxyethanone2-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(4-methylcyclohexyloxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(4-methylcyclohexyloxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Benzyloxy-1-[4-(S)-[3-(decahydronaphthalen-2-yloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone1-[4-(S)-[3-(Decahydronaphthalen-2-yloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone2-Benzyloxy-1-[4-(S)-[3-(bicyclohexyl-4-yloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone1-[4-(S)-[3-(Bicyclohexyl-4-yloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone2-Benzyloxy-1-(3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(4-trifluoromethylcyclohexyloxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(4-trifluoromethylcyclohexyloxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(3-methoxy-3-methylbutoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(3-methoxy-3-methylbutoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(1-phenylcyclopentylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(1-phenylcyclopentylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Benzyloxy-1-{3-(S)-(1-R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(1-phenylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(1-phenylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Benzyloxy-1-[(3S,4S)-4-3-(3-ethyloxetan-3-ylmethoxy)-4-methoxyphenyl]-3-((1R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone1-((3R)-3-((1R)-1-Hydroxyethyl)-4-{3-[(3-ethyloxetan-3-yl)methoxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)-2-hydroxyethan-1-one(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoethylacetate2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoethylacetate2-Benzyloxy-1-[(3S,4S)-4-[3-(2-biphenyl-4-ylethoxy)-4-methoxyphenyl]-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone1-[(3S,4S)-4-[3-(2-Biphenyl-4-ylethoxy)-4-methoxyphenyl]-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-oxoethylacetate2-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)-2-oxoethylacetate2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(dicyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl)-2-oxoethylacetate2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one1-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-{2-[2-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)-2-hydroxyethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(dicyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyethan-1-one1-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(3,3-dimethylbutoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(phenylmethoxy)ethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(3,3-dimethylbutoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(phenylmethoxy)ethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,49)-4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-oneN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoethyl)(phenylmethoxy)carboxamide1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-aminoethan-1-one2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1,1-dimethyl-2-oxoethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxy-2-methylpropan-1-one2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-methyl-2-oxoethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxypropan-1-one2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxo-1-phenylethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxy-2-phenylethan-1-one2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-(4-fluorophenyl)-2-oxoethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(4-fluorophenyl)-2-hydroxyethan-1-one({3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}carbonyl)-cyclopropylacetate3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinylhydroxycyclopropyl ketone2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-(methylpropyl)-2-oxoethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxy-3-methylpentan-1-one2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-(2-methylpropyl)-2-oxoethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxy-4-methylpentan-1-one2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-2-oxo-1-benzylethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxy-3-phenylpropan-1-one(1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxo-1-benzylethylacetate((2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxy-3-phenylpropan-1-one2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-methyl-2-oxoethylacetate2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-1-methyl-2-oxoethylacetate2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}(1S)-1-methyl-2-oxoethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxypropan-1-one2-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)-2-oxoethylacetate1-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)(2S)-2-hydroxypropan-1-one2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(4-methoxy-3-{3-[4-(trifluoromethyl)phenyl]prop-2-ynyloxy}phenyl)-3-methylpyrrolidinyl](1S)-1-methyl-2-oxoethylacetate1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(4-methoxy-3-{3-[4-(trifluoromethyl)phenyl]prop-2-ynyloxy}phenyl)-3-methylpyrrolidinyl](2S)-2-hydroxypropan-1-one2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-1-methyl-2-oxoethylacetate1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-hydroxypropan-1-one2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-(4-fluorophenyl)-2-oxoethylacetate1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(4-fluorophenyl)-2-hydroxyethan-1-one2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-methyl-2-oxoethylacetate1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxypropan-1-one2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1,1-dimethyl-2-oxoethylacetate1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxy-2-methylpropan-1-oneMethyl(3R)-3-((1R)-1-hydroxyethyl)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylate2-Hydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[2-(tetrahydrofuran-2-yl)ethoxy]phenyl}-3-methylpyrrolidin-1-yl)ethanone2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxy-ethyl)-4-[4-methoxy-3-(tetrahydrofuran-3-ylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanoneMethyl(3R)-3-((1R)-1-hydroxyethyl)-4-[3-((3S)oxolan-3-yloxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylateMethyl(3R)-3-((1R)-1-hydroxyethyl)-4-[3-((3R)oxolan-3-yloxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-{3-[2-(4-fluorophenoxy)ethoxy]-4-methoxyphenyl}-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenoxy)propoxy]-4-methoxyphenyl}-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(4-methoxy-3-prop-2-ynyloxyphenyl)-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-but-2-ynyloxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinecarboxylate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl)-2-acetylthioethan-1-one1-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-sulfanylethan-1-one{2-[(3S,4S)-3-((R)-1-Hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidin-1-yl]-2-oxo-ethyl)carbamicacid tert-butyl ester2-Amino-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[3-(4-trifluoromethylphenyl)-prop-2-ynyloxy]phenyl}-3-methylpyrrolidin-1-yl)ethanoneMethyl2-{3-((1R)-1-hydroxyethyl)(3S,4S)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoacetateMethyl2-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoacetateMethyl2-{3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-oxoacetate4-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(1,2-dihydroxyethyl)-3-methylpyrrolidine-1-carboxylicacid methyl ester[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-(2,2-dimethyl-[1,3]dioxolan-4-(S)-yl)methanone1-[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-(S)-3-dihydroxypropan-1-one(R)-2,3-Dihydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[3-(indan-2-ylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidin-1-yl}propan-1-one(R)-1-[(3S,4S)-4-{3-[3-(4-Fluorophenoxy)propoxy]-4-methoxyphenyl}-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2,3-dihydroxypropan-1-one1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[3-(4-trifluoromethylphenyl)prop-2-ynyloxy]phenyl}-3-methylpyrrolidin-1-yl)-methanone(R)-2,3-Dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[3-(4-trifluoromethylphenyl)-prop-2-ynyloxy]-phenyl}-3-methylpyrrolidin-1-yl)-propan-1-one2-Benzyloxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(2-thiophen-3-yl-ethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Hydroxy-1-{3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-((R)-2-phenylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone1-[(3S,4S)-4-[3-(3-Cyclopentylpropoxy)-4-methoxyphenyl]-3-((R)-1-hydroxyethyl)-4-methylpyrrolidin-1-yl]-2-hydroxyethanone2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylpropoxy)phenyl]-3-methylpyrrolidin-1-yl}-ethanone2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[3-(1-hydroxyindan-2-yloxy)-4-methoxyphenyl]-3-methylpyrrolidin-1-yl}ethanone2-Hydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[2-(4-methoxyphenyl)ethoxy]phenyl}-3-methylpyrrolidin-1-yl)ethanone2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-((R)-2-methylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone1-(R)-[1-(2-Benzyloxyethyl)-4-(S)-(3-cyclopentyloxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]-ethanol1-(R)-[4-(S)-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-hydroxyethyl)-3-(S)-methylpyrrolidin-3-yl]ethanol2-Benzyloxy-1-[4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-hydroxymethyl-3-methylpyrrolidin-1-yl]ethanone1-(2-Benzyloxyacetyl)-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidine-3-carbaldehyde1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-[(3S,4S)-3-((R)-1-hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidin-1-yl]methanone1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)-phenyl]-3-methylpyrrolidin[1[yl]}methanone(R)-2,3-Dihydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}propan-1-one1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-[(3S,4S)-3-((R)-1-hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidon-1-yl]methanone1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)-phenyl]-3-methylpyrrolidin-1-yl}methanone(S)-2,3-Dihydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-1-methylpyrrolidin-1-yl}propan-1-oneAcetic acid(S)-1-benzyl-2-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}-2-oxoethylester(S)-2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}-3-phenylpropan-1-oneMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylateand{2-[(3S,4S)-3-((R)-1-Hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidin-1-yl]-2-oxo-ethyl)carbamicacid tert-butyl ester.
 12. The compound of claim 1 selected from thegroup consisting of:1-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(phenylmethoxy)-ethan-1-one,1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxypentan-1-one,1-{(3S,4S)-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2R)-2-amino-3-hydroxypropan-1-onehydrochloride,1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxy-2-phenylethan-1-one,(S)-2,3-Dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}propan-1-one,and(S)-2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}-3-phenylpropan-1-one.13. The compound of claim 1 selected from the group consisting of:


14. A compound of claim 1 selected from the group consisting of:


15. The compound of claim 1 having an IC₅₀ vs. human recombinant PDE4 ofabout 700 pM to about 15 μM.
 16. The compound of claim 1 having aPBL/TNFα EC₅₀ of about 1 nM to about 20 μM.
 17. The compound of claim 1having an IC₅₀ vs. human recombinant PDE4 of about 700 pM to about 15μM, and a PBL/TNFα EC₅₀ of about 1 nM to about 20 μM.
 18. The compoundof claim 1 having an IC₅₀ vs. human recombinant PDE4 of about 100×10⁻⁹ Mor less.
 19. The compound of claim 1 having an IC₅₀ vs. humanrecombinant PDE4 of about 50×10⁻⁹ M or less.
 20. The compound of claim 1having a PBL/TNFα EC₅₀ of about 500×10⁻⁹ M or less.
 21. The compound ofclaim 1 having a PBL/TNFα EC₅₀, of about 100×10⁻⁹ M or less.
 22. Thecompound of claim 1 having an IC₅₀ vs. human recombinant PDE4 of about100×10⁻⁹ or less and a PBL/TNFα EC₅₀ of about 500×10⁻⁹ M or less. 23.The compound of claim 1 having an IC₅₀ vs. human recombinant PDE4 ofabout 50×10⁻⁹ or less and a PBL/TNFα EC₅₀ of about 100×10⁻⁹ M or less.24. A pharmaceutical composition comprising a compound of claim 1, apharmaceutically acceptable carrier, and, optionally, a secondantiinflammatory therapeutic agent.
 25. The composition of claim 24wherein the second antiinflammatory therapeutic agent is capable oftargeting TNFα.
 26. A compound having a formula:

wherein R¹ is selected from the group consisting of hydrogen, loweralkyl, bridged alkyl, aryl, cycloalkyl, a 4-, 5-, or 6-memberedsaturated heterocycle, heteroaryl, C₁₋₄alkylenearyl, C₁₋₄alkyleneOaryl,C₁₋₄alkyleneheteroaryl, C₁₋₄alkyleneHet, C₂₋₄alkylenearylOaryl,C₁₋₄alkylene bridged alkyl, C₁₋₄alkylenecycloalkyl, substituted orunsubstituted propargyl, substituted or unsubstituted allyl, andhalocycloalkyl; R² is selected from the group consisting of hydrogen,methyl, and halo-substituted methyl; R³ is selected from the groupconsisting of hydrogen, C₁₋₄alkylenearyl, andC(═O)C₁₋₃alkyleneOC₁₋₃-alkylenearyl; R⁴ is selected from the groupconsisting of hydrogen, lower alkyl, haloalkyl, cycloalkyl, and aryl; R⁵is selected from the group consisting of hydrogen, lower alkyl, alkynyl,haloalkyl, hydroxyalkyl, cycloalkyl, and aryl; R⁶ is selected from thegroup consisting of hydrogen, lower alkyl, and C(═O)R⁷; R⁷ is selectedfrom the group consisting of lower alkyl, branched or unbranched,C₁₋₄alkylenearyl, cycloalkyl, Het, C₁₋₄alkylenecycloalkyl, heteroaryl,and aryl, each optionally substituted with one or more of OC(═O)R⁸,C(═O)OR⁸, OR⁸, NR⁸R⁹, and SR⁸; and R⁸ and R⁹, same or different, areselected from the group consisting of hydrogen, lower alkyl, cycloalkyl,aryl, heteroaryl, C(═O)Oalkyl, C(═O)-alkyl, C(═O)Oaryl, alkylSO₂,haloalkylSO₂, C(═O)—C₁₋₃alkylenearyl, C(═O)OC₁₋₄alkylenearyl,C₁₋₄alkylenearyl, and Het, or R⁸ and R⁹ together form a 4-membered to7-membered ring; R¹⁰ is selected from the group consisting of hydrogen,alkyl, haloalkyl, cycloalkyl, aryl, C(═O)alkyl, C(═O)cycloalkyl,C(═O)aryl, C(═O)Oalkyl, C(═O)Ocycloalkyl, C(═O)aryl, CH₂OH, CH₂Oalkyl,CHO, CN, NO₂, and SO₂R¹¹; and R¹¹ is selected from the group consistingof alkyl, cycloalkyl, trifluoromethyl, aryl, aralkyl, and NR⁸R⁹; andsalts and solvates thereof.
 27. The compound of claim 26 selected fromthe group consisting of:2-[1-Benzyl-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]propan-2-ol2-[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]propan-2-ol2-Benzyloxy-1-[4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(1-hydroxy-1-methylethyl)-3-(S)-methyl-pyrrolidin-1-yl]ethanone(1R)-1-[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidin-3-yl]ethan-1-ol(1R)-1-[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]ethan-1-ol(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidin-3-yl]ethan-1-ol(1S)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidin-3-yl]ethan-1-ol(1S)-1-{(3S,4S)-4-[4-Methoxy-3-(phenylmethoxy)phenyl]-3-methyl-1-benzylpyrrolidin-3-yl}ethan-1-ol(1R)-1-{(3S,4S)-4-[4-Methoxy-3-(phenylmethoxy)phenyl]-3-methyl-1-benzylpyrrolidin-3-yl}ethan-1-ol1-R-[1-Benzyl-4-S-(3-tert-butoxy-4-methoxyphenyl)-3-S-methylpyrrolidin-3-yl]ethanol3-[1-Benzyl-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidine-3-carbonyl]-4-(R)-phenyloxazolidin-2-one1-[1-Benzyl-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]ethanol(1R)-1-{(3S,4S)-4-[3-(Cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidin-3-yl}ethan-1-ol(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]ethan-1-ol(1S)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]ethan-1-ol5-[4-((1R)-1-Hydroxyethyl)(3S,4S)-4-methylpyrrolidin-3-yl]-2-methoxyphenol(1R)-1-{(3R)-4-[3-(tert-Butoxy)-4-methoxyphenyl]-3-methyl-1-benzylpyrrolidin-3-yl}ethan-1-ol5-[(4R)-4-((1S)-1-Hydroxyethyl)-4-methyl-1-benzylpyrrolidin-3-yl]-2-methoxyphenoland[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]methanol.